Pyridines and pyrimidines and use thereof

ABSTRACT

The present disclosure provides pyridines and pyrimidines of Formula I and pharmaceutically acceptable salts and solvates thereof: wherein A, G, W 1 , W 2 , W 3 , and R 5  are defined as set forth in the specification. The present disclosure also provides uses of the compounds of Formula I and pharmaceutically acceptable salts and solvates thereof. In certain embodiments, Compounds of the present disclosure are useful for treating pain. In another embodiment, Compounds of the present disclosure are useful for treating a disorder responsive to blockade of sodium channels, or alleviating symptoms of the disorder.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the U.S. national phase, pursuant to 35 U.S.C. §371, of PCT International Application Ser. No. PCT/US2015/012591, filedon Jan. 23, 2015, designating the United States and published in Englishon Jul. 30, 2015 as publication WO 2015/112801 A1, which claims priorityto U.S. Provisional Application Ser. No. 61/931,144, filed on Jan. 24,2014. The contents of the afore-mentioned patent applications areincorporated herein by their entirety.

BACKGROUND OF THE INVENTION

Voltage-gated sodium channels (VGSCs) are found in all excitable cells.In neuronal cells of the central nervous system (CNS) and peripheralnervous system (PNS) sodium channels are primarily responsible forgenerating the rapid upstroke of the action potential. In this mannersodium channels are essential to the initiation and propagation ofelectrical signals in the nervous system. Proper function of sodiumchannels is therefore necessary for normal function of the neuron.Consequently, aberrant sodium channel function is thought to underlie avariety of medical disorders (See Hubner et al., Hum. Mol. Genet.11:2435-2445 (2002) for a general review of inherited ion channeldisorders) including epilepsy (Yogeeswari et al, Curr. Drug Target5:589-602 (2004)), arrhythmia (Noble, Proc. Natl. Acad. Sci. USA99:5755-5756 (2002)), myotonia (Cannon, Kidney Int. 57:772-779 (2000)),and pain (Wood et al., J. Neurobiol., 61:55-71 (2004)).

VGSCs are composed of one α-subunit, which forms the core of the channeland is responsible for voltage-dependent gating and ion permeation, andseveral auxiliary β-subunits (see, e.g., Chahine et al., CNS &Neurological Disorders-Drug Targets 7:144-158 (2008) and Kyle and Ilyin,J. Med. Chem. 50:2583-2588 (2007)). α-Subunits are large proteinscomposed of four homologous domains. Each domain contains six α-helicaltransmembrane spanning segments. There are currently nine known membersof the family of voltage-gated sodium channel α-subunits. Names for thisfamily include SCNx, SCNAx, and Na_(v)x.x (see TABLE 1, below). The VGSCfamily has been phylogenetically divided into two subfamilies Na_(v)1.x(all but SCN6A) and Na_(v)2.x (SCN6A). The Na_(v)1.x subfamily can befunctionally subdivided into two groups, those which are sensitive toblocking by tetrodotoxin (TTX-sensitive or TTX-s) and those which areresistant to blocking by tetrodotoxin (TTX-resistant or TTX-r). Thereare three members of the subgroup of TTX-resistant sodium channels. TheSCN5A gene product (Na_(v)1.5, Hl) is almost exclusively expressed incardiac tissue and has been shown to underlie a variety of cardiacarrhythmias and other conduction disorders (Liu et al., Am. J.Pharmacogenomics 3:173-179 (2003)). Consequently, blockers of Na_(v)1.5have found clinical utility in treatment of such disorders (Srivatsa etal., Curr. Cardiol. Rep. 4:401-410 (2002)). The remaining TTX-resistantsodium channels, Na_(v)1.8 (SCN10A, PN3, SNS) and Na_(v)1.9 (SCN11A,NaN, SNS2) are expressed in the peripheral nervous system and showpreferential expression in primary nociceptive neurons. Human geneticvariants of these channels have not been associated with any inheritedclinical disorder. However, aberrant expression of Na_(v)1.8 has beenfound in the CNS of human multiple sclerosis (MS) patients and also in arodent model of MS (Black et al., Proc. Natl. Acad. Sci. USA97:11598-115602 (2000)). Evidence for involvement in nociception is bothassociative (preferential expression in nociceptive neurons) and direct(genetic knockout). Na_(v)1.8-null mice exhibited typical nociceptivebehavior in response to acute noxious stimulation but had significantdeficits in referred pain and hyperalgesia (Laird et al., J. Neurosci.22:8352-8356 (2002)).

TABLE 1 Voltage-gated sodium channel gene family Tissue Disease GeneDistri- TTX IC₅₀ Asso- Type Symbol bution (nM) ciation IndicationsNa_(v)1.1 SCN1A CNS/PNS 10 Epilepsy Pain, seizures, neuro- degenerationNa_(v)1.2 SCN2A CNS 10 Epilepsy Epilepsy, neuro- degeneration Na_(v)1.3SCN3A CNS 15 — Pain Na_(v)1.4 SCN4A Skeletal 25 Myotonia Myotonia muscleNa_(v)1.5 SCN5A Heart 2,000 Arrhyth- Arrhythmia muscle mia Na_(v)1.6SCN8A CNS/ 6 — Pain, PNS movement disorders Na_(v)1.7 SCN9A PNS 25Eryther- Pain malgia Na_(v)1.8 SCN10A PNS 50,000 — Pain Na_(v)1.9 SCN11APNS 1,000 — Pain

The Na_(v)1.7 (PN1, SCN9A) VGSC is sensitive to blocking by tetrodotoxinand is preferentially expressed in peripheral sympathetic and sensoryneurons. The SCN9A gene has been cloned from a number of species,including human, rat, and rabbit and shows 90% amino acid identitybetween the human and rat genes (Toledo-Aral et al., Proc. Natl. Acad.Sci. USA 94:1527-1532 (1997)).

An increasing body of evidence suggests that Na_(v)1.7 plays a key rolein various pain states, including acute, inflammatory and/or neuropathicpain. Deletion of the SCN9A gene in nociceptive neurons of mice led toan increase in mechanical and thermal pain thresholds and reduction orabolition of inflammatory pain responses (Nassar et al., Proc. Natl.Acad. Sci. USA 101:12706-12711 (2004)).

Sodium channel-blocking agents have been reported to be effective in thetreatment of various disease states, and have found particular use aslocal anesthetics, e.g., lidocaine and bupivacaine, and in the treatmentof cardiac arrhythmias, e.g., propafenone and amiodarone, and epilepsy,e.g., lamotrigine, phenytoin and carbamazepine (see Clare et al., DrugDiscovery Today 5:506-510 (2000); Lai et al., Annu. Rev. Pharmacol.Toxicol. 44:371-397 (2004); Anger et al., J. Med. Chem. 44:115-137(2001), and Catterall, Trends Pharmacol. Sci. 8:57-65 (1987)). Each ofthese agents is believed to act by interfering with the rapid influx ofsodium ions.

Other sodium channel blockers such as BW619C89 and lifarizine have beenshown to be neuroprotective in animal models of global and focalischemia (Graham et al., J. Pharmacol. Exp. Ther. 269:854-859 (1994);Brown et al., British J. Pharmacol. 115:1425-1432 (1995)).

It has also been reported that sodium channel-blocking agents can beuseful in the treatment of pain, including acute, chronic, inflammatory,neuropathic, and other types of pain such as rectal, ocular, andsubmandibular pain typically associated with paroxysmal extreme paindisorder; see, for example, Kyle and Ilyin., J. Med. Chem. 50:2583-2588(2007); Wood et al., J. Neurobiol. 61:55-71 (2004); Baker et al., TRENDSin Pharmacological Sciences 22:27-31 (2001); and Lai et al., CurrentOpinion in Neurobiology 13:291-297 (2003); the treatment of neurologicaldisorders such as epilepsy, seizures, epilepsy with febrile seizures,epilepsy with benign familial neonatal infantile seizures, inheritedpain disorders, e.g., primary erthermalgia and paroxysmal extreme paindisorder, familial hemiplegic migraine, and movement disorder; and thetreatment of other psychiatric disorders such as autism, cerebellaratrophy, ataxia, and mental retardation; see, for example, Chahine etal., CNS & Neurological Disorders-Drug Targets 7:144-158 (2008) andMeister and Kearney, J. Clin. Invest. 115:2010-2017 (2005). In additionto the above-mentioned clinical uses, carbamazepine, lidocaine andphenytoin are used to treat neuropathic pain, such as from trigeminalneuralgia, diabetic neuropathy and other forms of nerve damage (Taylorand Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)). Furthermore,based on a number of similarities between chronic pain and tinnitus,(Moller, Am. J. Otol. 18:577-585 (1997); Tonndorf, Hear. Res. 28:271-275(1987)) it has been proposed that tinnitus should be viewed as a form ofchronic pain sensation (Simpson, et al., Tip. 20:12-18 (1999)). Indeed,lidocaine and carbamazepine have been shown to be efficacious intreating tinnitus (Majumdar, B. et al., Clin. Otolaryngol. 8:175-180(1983); Donaldson, Laryngol. Otol. 95:947-951 (1981)).

Many patients with either acute or chronic pain disorders respond poorlyto current pain therapies, and the development of resistance orinsensitivity to opiates is common. In addition, many of the currentlyavailable treatments have undesirable side effects.

In view of the limited efficacy and/or unacceptable side-effects of thecurrently available agents, there is a pressing need for more effectiveand safer analgesics that work by blocking sodium channels.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides pyridines and pyrimidinesrepresented by Formulae I-V, provided below, and pharmaceuticallyacceptable salts and solvates thereof, collectively referred to hereinas “Compounds of the Disclosure.”

In another aspect, the present disclosure provides the use of Compoundsof the Disclosure as blockers of one or more sodium (Na⁺) channels.

In another aspect, the present disclosure provides compounds assynthetic intermediates that can be used to prepare blockers of one ormore sodium (Na⁺) channels.

In another aspect, the present disclosure provides a method for treatingor alleviating symptoms thereof of a disorder responsive to the blockadeof one or more sodium channels in a mammal, comprising administering tothe mammal an effective amount of a Compound of the Disclosure.

In another aspect, the present disclosure provides a method for treatingpain (e.g., acute pain, chronic pain, which includes but is not limitedto, neuropathic pain, postoperative pain, and inflammatory pain, orsurgical pain), comprising administering an effective amount of aCompound of the Disclosure to a mammal in need of such treatment.Specifically, the present disclosure provides a method for preemptive orpalliative treatment of pain by administering an effective amount of aCompound of the Disclosure to a mammal in need of such treatment.

In another aspect, the present disclosure provides a method for treatingstroke, neuronal damage resulting from head trauma, epilepsy, seizures,general epilepsy with febrile seizures, severe myoclonic epilepsy ininfancy, neuronal loss following global and focal ischemia, migraine,familial primary erythromelalgia, paroxysmal extreme pain disorder,cerebellar atrophy, ataxia, dystonia, tremor, mental retardation,autism, a neurodegenerative disorder (e.g., Alzheimer's disease,amyotrophic lateral sclerosis (ALS), or Parkinson's disease), manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or alleviating symptoms thereof, or providing localanesthesia, comprising administering an effective amount of a Compoundof the Disclosure to a mammal in need of such treatment.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a Compound of the Disclosure and one or morepharmaceutically acceptable carriers.

In another aspect, the present disclosure provides a pharmaceuticalcomposition for treating a disorder responsive to the blockade of sodiumion channels, wherein the pharmaceutical composition comprises aneffective amount of a Compound of the Disclosure in a mixture with oneor more pharmaceutically acceptable carriers.

In another aspect, the present disclosure provides a method ofmodulating sodium channels in a mammal, comprising administering to themammal an effective amount of at least one Compound of the Disclosure.

In another aspect, the present disclosure provides Compounds of theDisclosure for use in treating pain in a mammal, e.g., acute pain,chronic pain, which includes but is not limited to, neuropathic pain,postoperative pain, and inflammatory pain, or surgical pain.

In another aspect, the present disclosure provides Compounds of theDisclosure for use in treating stroke, neuronal damage resulting fromhead trauma, epilepsy, seizures, general epilepsy with febrile seizures,severe myoclonic epilepsy in infancy, neuronal loss following global andfocal ischemia, migraine, familial primary erythromelalgia, paroxysmalextreme pain disorder, cerebellar atrophy, ataxia, dystonia, tremor,mental retardation, autism, a neurodegenerative disorder (e.g.,Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or Parkinson'sdisease), manic depression, tinnitus, myotonia, a movement disorder, orcardiac arrhythmia, or alleviating symptoms thereof, or providing localanesthesia, in a mammal.

In another aspect, the present disclosure provides a radiolabeledCompound of the Disclosure and the use of such compounds as radioligandsin any appropriately selected competitive binding assays and screeningmethodologies. Thus, the present disclosure further provides a methodfor screening a candidate compound for its ability to bind to a sodiumchannel or sodium channel subunit using a radiolabeled Compound of theDisclosure. In certain embodiments, the compound is radiolabeled with³H, ¹¹C, or ¹⁴C. This competitive binding assay can be conducted usingany appropriately selected methodology. In one embodiment, the screeningmethod comprises: i) introducing a fixed concentration of theradiolabeled compound to an in vitro preparation comprising a soluble ormembrane-associated sodium channel, subunit or fragment under conditionsthat permit the radiolabeled compound to bind to the channel, subunit orfragment, respectively, to form a conjugate; ii) titrating the conjugatewith a candidate compound; and iii) determining the ability of thecandidate compound to displace the radiolabeled compound from saidchannel, subunit or fragment.

In another aspect, the present disclosure provides a Compound of theDisclosure for use in the manufacture of a medicament for treating painin a mammal. In one embodiment, the present disclosure provides the useof a Compound of the Disclosure in the manufacture of a medicament forpalliative or preemptive treatment of pain, such as acute pain, chronicpain, or surgical pain.

In another aspect, the present disclosure provides a Compound of theDisclosure for use in the manufacture of a medicament for treatingstroke, neuronal damage resulting from head trauma, epilepsy, seizures,general epilepsy with febrile seizures, severe myoclonic epilepsy ininfancy, neuronal loss following global and focal ischemia, migraine,familial primary erythromelalgia, paroxysmal extreme pain disorder,cerebellar atrophy, ataxia, dystonia, tremor, mental retardation,autism, a neurodegenerative disorder (e.g., Alzheimer's disease,amyotrophic lateral sclerosis (ALS), or Parkinson's disease), manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia, in a mammal.

Additional embodiments and advantages of the disclosure will be setforth, in part, in the description that follows, and will flow from thedescription, or can be learned by practice of the disclosure. Theembodiments and advantages of the disclosure will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only, and are notrestrictive of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present disclosure is based on the use of Compounds ofthe Disclosure as blockers of sodium (Na⁺) channels. In view of thisproperty, the Compounds of the Disclosure are useful for treatingdisorders responsive to the blockade of sodium ion channels.

In one embodiment, Compounds of the Disclosure are compounds representedby Formula I:

and the pharmaceutically acceptable salts and solvates thereof,

wherein:

G is selected from the group consisting of cyano, dihydroxyalkyl,—C(═O)E, —CH(OH)CH(OH)C(═O)E, and —CH(OH)C(═O)E;

E is selected from the group consisting of hydrogen, hydroxy, alkoxy,dihydroxyalkyl, and —NR^(1a)R^(1b);

R^(1a) is selected from the group consisting of hydrogen, alkyl,optionally substituted aralkyl, optionally substituted(heterocyclo)alkyl, optionally substituted (heteroaryl)alkyl,(amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl,(carboxamido)alkyl, (cyano)alkyl, alkoxyalkyl, hydroxyalkyl, andheteroalkyl;

R^(1b) is selected from the group consisting of hydrogen and alkyl; or

R^(1a) and R^(1b) taken together with the nitrogen atom to which theyare attached form a 3- to 8-membered optionally substituted heterocyclo;

W¹, W², and W³ are each independently selected from the group consistingof N and CR²; with the proviso that at least one of W¹, W², and W³ is N;

R² is selected from the group consisting of hydrogen, halo, and alkyl;

A is selected from the group consisting of:

R^(3a) is selected from the group consisting of hydrogen, alkyl,heteroalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl,(alkoxy)alkyl, optionally substituted cycloalkyl, optionally substitutedheterocyclo, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aralkyl, carboxamido, optionallysubstituted alkylcarbonyl, optionally substituted (alkoxy)carbonyl, and—SO₂R^(6c);

R^(3b) is selected from the group consisting of optionally substitutedaryl, optionally substituted aralkyl, and optionally substitutedheteroaryl;

R^(3c) is selected from the group consisting of hydrogen and hydroxy;with the proviso that when R^(3c) is hydroxy, then

is a single bond;

Z¹ is selected from the group consisting of —(C═O)—(CH₂)_(k)—,—(CH₂)_(m)—, —(CH₂)_(n)—O—(CH₂)_(o)—, and —(CH₂)_(p)—N(R⁴)—(CH₂)_(q)—;

k is 1, 2, or 3;

m is 2, 3, 4, 5, or 6;

n is 2, 3, or 4;

o is 0, 1, or 2;

p is 2, 3, or 4;

q is 0, 1, or 2

Z² is selected from the group consisting of —(CH₂)_(r)— and—(CH₂)_(s)—Y¹—;

Y¹ is selected from the group consisting of —NR¹¹ and O;

r is 1, 2, or 3;

s is 1, 2, or 3;

is a single or double bond;

R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl,(dialkylamino)alkyl, optionally substituted aralkyl, optionallysubstituted (heteroaryl)alkyl, optionally substituted (cycloalkyl)alkyl,(cyano)alkyl, (carboxamido)alkyl, —COR^(6a), and —SO₂R^(6b);

R^(6a) is selected from the group consisting of alkyl, alkoxy,hydroxyalkyl, optionally substituted cycloalkyl, optionally substitutedaryl, amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl,and (dialkylamino)alkyl;

R^(6b) is selected from the group consisting of alkyl, optionallysubstituted cycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl;

R^(6c) is selected from the group consisting of alkyl, optionallysubstituted cycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl;

R⁵ is selected from the group consisting of hydrogen, halo, alkyl,hydroxyalkyl, cyano, heterocyclo, and —X—R⁷;

X is selected from the group consisting of —O—, —NR^(8a)—, and—(CH₂)_(t)—Y²—;

Y² is selected from the group consisting of —O— and —NR^(8b)—;

t is 1, 2, 3 or 4;

R⁷ is selected from the group consisting of hydrogen, alkyl,hydroxyalkyl,

R^(8a) is selected from the group consisting of hydrogen and alkyl;

R^(8b) is selected from the group consisting of hydrogen and alkyl; or

R^(8b) and R⁷ taken together with the nitrogen atom to which they areattached form a 3- to 8-membered optionally substituted heterocyclo;

R⁹ is selected from the group consisting of hydrogen, alkyl, andhydroxyalkyl;

R^(10a) and R^(10b) are independently selected from the group consistingof hydrogen and alkyl; or

R^(10a) and R^(10b) taken together with the nitrogen atom to which theyare attached form a 3- to 8-membered optionally substituted heterocyclo;and

R¹¹ is selected from the group consisting of hydrogen and alkyl.

In Formula I, when Z¹ is —(C═O)—(CH₂)_(k)—, then the carbonyl isattached to —NR^(3a)—; when Z² is —(CH₂)_(s)—Y¹—, then —Y¹— is attachedthe phenyl ring; and when X is —(CH₂)_(t)—Y²—, then —Y²— is attached to—R⁷.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I and the pharmaceutically acceptable salts andsolvates thereof, wherein, when Z¹ is —(CH₂)_(p)—N(R⁴)—(CH₂)_(q)—, p is2, and q is 1, then R⁴ is —COR^(6a) or —SO₂R^(6b).

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula II:

and the pharmaceutically acceptable salts and solvates thereof, whereinR^(3a), Z¹, W¹, W², W³, R⁵, and G are as defined above in connectionwith Formula I.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula II, wherein Z¹ is —(CH₂)_(m)—, and thepharmaceutically acceptable salts and solvates thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula II, wherein Z¹ is of —(C═O)—(CH₂)_(k)—, and thepharmaceutically acceptable salts and solvates thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula II, wherein Z¹ is —(CH₂)_(n)—(CH₂)_(o)—, and thepharmaceutically acceptable salts and solvates thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula II, wherein Z¹ is —(CH₂)_(p)—N(R⁴)—(CH₂)_(q)—,and the pharmaceutically acceptable salts and solvates thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula II, wherein:

is selected from the group consisting of:

and the pharmaceutically acceptable salts and solvates thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula II, wherein:

is A-6, and R⁴ is selected from the group consisting of —COR^(6a) and—SO₂R^(6b), and the pharmaceutically acceptable salts and solvatesthereof. In one embodiment, R⁴ is —COR^(6a). In another embodiment, R⁴is —SO₂R^(6b). In a certain embodiment, R^(6b) is alkyl (e.g., methyl,ethyl, and propyl).

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula II, wherein R^(3a) is selected from the groupconsisting of alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocyclo, optionally substituted aryl, and optionallysubstituted heteroaryl, or a pharmaceutically acceptable salt or solvatethereof. In one embodiment, R^(3a) is optionally substituted phenyl. Inanother embodiment, R^(3a) is alkyl, including, such as, (C₁-C₆)akyl. Ina certain embodiment, R^(3a) is isopropyl.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula II, wherein R^(3a) is —SO₂R^(6c), and thepharmaceutically acceptable salts and solvates thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula III:

and the pharmaceutically acceptable salts and solvates thereof, whereinR^(3b), W¹, W², W³, R⁵, G, and

are as defined above in connection with Formula I.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula IV:

and the pharmaceutically acceptable salts and solvates thereof, whereinR^(3b), W¹, W², W³, R⁵, G, and

are as defined above in connection with Formula I. In one embodiment,R^(3c) is hydrogen. In one embodiment, R^(3c) is hydroxy.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula V:

and the pharmaceutically acceptable salts and solvates thereof, whereinR^(3b), W¹, W², W³, R⁵, G, and

are as defined above in connection with Formula I. In one embodiment,R^(3c) is hydrogen. In one embodiment, R^(3c) is hydroxy.

In one embodiment, Compounds of the Disclosure are compounds representedby any one of Formulae III-V, wherein R^(3b) is optionally substitutedphenyl, and the pharmaceutically acceptable salts and solvates thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae III-V, wherein R^(3b) is optionallysubstituted aralkyl, and the pharmaceutically acceptable salts andsolvates thereof.

In still another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae III-V, wherein R^(3b) is optionallysubstituted heteroaryl, and the pharmaceutically acceptable salts andsolvates thereof.

In a separate embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae I-V, wherein R² is hydrogen, and thepharmaceutically acceptable salts and solvates thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae I-V, wherein W¹ is N, W² is CH, andW³ is CH, and the pharmaceutically acceptable salts and solvatesthereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae I-V, wherein W¹ is N, W² is N, and W³is CH, and the pharmaceutically acceptable salts and solvates thereof.

In yet another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae I-V, W¹ is CH, W² is CH, and W³ is N,and the pharmaceutically acceptable salts and solvates thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae I-V, wherein G is dihydroxyalkyl, andthe pharmaceutically acceptable salts and solvates thereof. In oneembodiment, G is a dihydroxyalkyl selected from the group consisting of:

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae I-V, wherein G is—CH(OH)CH(OH)C(═O)E, and the pharmaceutically acceptable salts andsolvates thereof. In one embodiment, is —CH(OH)CH(OH)C(═O)E selectedfrom the group consisting of:

and the pharmaceutically acceptable salts and solvates thereof. In oneembodiment, E is —NR^(1a)R^(1b). In one embodiment, E is —NH₂.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae I-V, wherein G is —CH(OH)C(═O)E, andthe pharmaceutically acceptable salts and solvates thereof. In oneembodiment, G is —CH(OH)C(═O)E selected from the group consisting of:

and the pharmaceutically acceptable salts and solvates thereof. In oneembodiment, E is —NR^(1a)R^(1b). In one embodiment, E is —NH₂.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae I-V, wherein G is —C(═O)E, and thepharmaceutically acceptable salts and solvates thereof. In oneembodiment, E is —NR^(1a)R^(1b). In one embodiment, E is —NH₂. In oneembodiment, E is dihydroxyalkyl. In one embodiment, E is adihydroxyalkyl selected from the group consisting of:

In one embodiment, Compounds of the Disclosure are compounds representedby any one of Formulae I-V, wherein R⁵ is selected from the groupconsisting of hydrogen, hydroxyalkyl, and —X—R⁷, and thepharmaceutically acceptable salts and solvates thereof.

In one embodiment, Compounds of the Disclosure are compounds representedby any one of Formulae I-V, wherein R⁵ is hydrogen, and thepharmaceutically acceptable salts and solvates thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae I-V, wherein R⁵ is hydroxyalkyl, andthe pharmaceutically acceptable salts and solvates thereof. In oneembodiment, R⁵ is dihydroxyalkyl. In one embodiment, R⁵ isdihydroxyalkyl selected from the group consisting of:

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae I-V, wherein R⁵ is —X—R⁷, and thepharmaceutically acceptable salts and solvates thereof. In oneembodiment, X is —O—. In one embodiment, X is —NH—. In one embodiment, Xis —CH₂—NH— (wherein the —NH— is attached to —R⁷). In one embodiment, Xis —CH₂—O— (wherein the —O— is attached to —R⁷).

In still another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae I-V, wherein R⁵ is —X—R⁷ and R⁷ isselected from the group consisting of:

and the pharmaceutically acceptable salts and solvates thereof. In oneembodiment, R⁹ is alkyl.

In another embodiment, Compounds of the Disclosure are compounds ofTABLE 2, and the pharmaceutically acceptable salts and solvates thereof.

TABLE 2 Cpd # Structure Chemical name  58

6-(1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7- yl)picolinamide  59

tert-butyl 7-(6-carbamoylpyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4- carboxylate  60

tert-butyl (S)-7-(6-(1,2- dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4- carboxylate  61

6-(1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydrobenzo[e][1,4]oxazepin-7- yl)picolinamide  62

(S)-1-(6-(1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydrobenzo[e][1,4]oxazepin-7-yl)pyridin-2-yl)ethane-1,2-diol  63

(S)-6-((1-amino-1-oxopropan-2- yl)amino)-2-(5-(4-(trifluoromethyl)phenyl)-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-8-yl)pyrimidine-4-carboxamide  64

(S)-6-((1-amino-1-oxopropan-2- yl)amino)-2-(1-(4-(trifluoro-methyl)phenyl)-2,3,4,5-tetrahydro-1H- benzo[b]azepin-7-yl)pyrimidine-4-carboxamide  65

6-(5-(4-(trifluoromethyl)-phenyl)- 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-8- yl)picolinamide  66

6-(1-(4-(trifluoromethyl)-phenyl)- 1,2,3,4-tetrahydroquinolin-6-yl)picolinamide  67

6-(1-(3-(trifluoromethyl)-phenyl)- 1,2,3,4-tetrahydroquinolin-6-yl)picolinamide  68

6-(1-(4-(trifluoromethyl)-phenyl)indolin- 5-yl)-picolinamide  69

6-(4-(4-(trifluoromethyl)-phenyl)-2H- chromen-7-yl)picolinamide  70

(S)-6-((1-amino-1-oxopropan-2- yl)amino)-2-(4-(4-(trifluoro-methyl)phenyl)-2H-chromen-7- yl)pyrimidine-4-carboxamide  71

6-(((S)-1-amino-1-oxopropan-2- yl)amino)-2-((3R,4S)-3-hydroxy-4-(4-(trifluoromethyl)phenyl)chroman-7- yl)pyrimidine-4-carboxamide  72

(S)-6-(((2-oxopyrrolidin-3- yl)amino)methyl)-2-(5-(4-(trifluoromethyl)phenyl)-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-8-yl)pyrimidine-4-carboxamide  73

(S)-1-(6-(1-cyclohexyl-2,3,4,5- tetrahydro-1H-benzo[b]azepin-7-yl)pyridin-2-yl)ethane-1,2-diol  74

(S)-6-((1-amino-1-oxopropan-2- yl)amino)-2-(1-cyclohexyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7- yl)pyrimidine-4-carboxamide  75

(S)-1-(6-(1-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7- yl)pyridin-2-yl)ethane-1,2-diol 76

(S)-1-(6-(1-(4,4-difluorocyclohexyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7- yl)pyridin-2-yl)ethane-1,2-diol 77

(S)-5-(6-(1,2-dihydroxyethyl)pyridin-2- yl)-1-(4-(trifluoromethyl)-benzyl)indolin-2-one  78

(S)-1-(6-(1-((4-(trifluoromethyl)- phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-2- yl)ethane-1,2-diol  79

tert-butyl (S)-7-(4-((1-amino-1- oxopropan-2-yl)amino)-6-carbamoylpyrimidin-2-yl)-1-(4- (trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4- carboxylate  80

(S)-6-((1-amino-1-oxopropan-2- yl)amino)-2-(1-(4-(trifluoro-methyl)phenyl)-1,2,3,4- tetrahydroquinolin-6-yl)pyrimidine-4-carboxamide  81

(S)-1-(6-(1-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinolin-6-yl)pyridin- 2-yl)ethane-1,2-diol  82

(S)-6-((2-oxopyrrolidin-3-yl)oxy)-2-(5-(4-(trifluoromethyl)phenyl)-2,3,4,5- tetrahydrobenzo-[b][1,4]oxazepin-8-yl)pyrimidine-4-carboxamide  83

(2R,3S)-2,3-dihydroxy-3-(6-(5-(4- (trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[b][1,4]-oxazepin-8- yl)pyridin-2-yl)propanamide  84

6-(1-(4-(trifluoromethyl)-phenyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)picolinamide  85

6-(4-methyl-1-(4- (trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7- yl)picolinamide  86

(S)-1-(6-(1-(4-(trifluoromethyl)phenyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyridin-2- yl)ethane-1,2-diol  87

(S)-1-(6-(4-(cyclopropylmethyl)-1-(4- (trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7- yl)pyridin-2-yl)ethane-1,2-diol 88

(S)-6-((1-amino-1-oxopropan-2- yl)amino)-2-(1-(4-(trifluoromethyl)phenyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyrimidine-4-carboxamide  89

(S)-6-((1-amino-1-oxopropan-2- yl)amino)-2-(4-(cyclopropylmethyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7- yl)pyrimidine-4-carboxamide  90

(S)-6-((1-amino-1-oxopropan-2- yl)amino)-2-(4-methyl-1-(4-(trifluoromethyl)phenyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyrimidine-4-carboxamide  91

6-(4-acetyl-1-(4- (trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7- yl)picolinamide  92

7-(6-carbamoylpyridin-2-yl)-N,N- diethyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H- benzo[e][1,4]diazepino-4-carboxamide  93

6-(4-(cyclopropanecarbonyl)-1-(4- (trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7- yl)picolinamide  94

(S)-1-(1-cyclohexyl-7-(6-(1,2- dihydroxyethyl)pyridin-2-yl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4- yl)ethan-1-one  95

(S)-1-(6-(4-(methylsulfonyl)-1-(4- (trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7- yl)pyridin-2-yl)ethane-1,2-diol 96

(S)-1-(7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)- 1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)ethan-1-one  97

(S)-7-(6-(1,2-dihydroxyethyl)pyridin-2- yl)-N-ethyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,5- tetrahydro-4H-benzo[e][1,4]diazepin-4-carboxamide  98

(S)-7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)- 1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-carboxamide  99

(S)-1-(7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)- 1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2- hydroxyethan-1-one 100

(S)-1-(7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)- 1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2- (dimethylamino)ethan-1-one 102

6-(4-(cyanomethyl)-1-(4- (trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7- yl)picolinamide 103

(S)-2-(7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)- 1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)acetamide 104

(S)-2-(1-cyclohexyl-7-(6-(1,2- dihydroxyethyl)pyridin-2-yl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4- yl)acetamide 105

(S)-2-(7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)- 1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-N- methylacetamide 106

(S)-2-(7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)- 1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)acetonitrile 107

(S)-1-(6-(4-((1H-imidazol-2-yl)methyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7- yl)pyridin-2-yl)ethane-1,2-diol108

6-(4-allyl-1-(4-(trifluoromethyl)phenyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)picolinamide 109

6-(4-(2,3-dihydroxypropyl)-1-(4- (trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7- yl)picolinamide 110

6-(4-(4-(trifluoromethyl)- phenyl)chroman-7-yl)-picolinamide 111

6-(((S)-1-amino-1-oxopropan-2- yl)amino)-2-(4-(4-(trifluoromethyl)phenyl)chroman-7- yl)pyrimidine-4-carboxamide 112

6-(((S)-1-amino-1-oxopropan-2- yl)amino)-2-(4-(4-fluorobenzyl)chroman-7-yl)pyrimidine- 4-carboxamide 121

(S)-6-(4-(cyclopropylmethyl)-1-(4- (trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7- yl)-4-(1,2-dihydroxyethyl)-picolinonitrile 122

(S)-6-(4-(cyclopropylmethyl)-1-(4- (trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7- yl)-4-(1,2-dihydroxyethyl)-picolinamide 123

(S)-4-(4-(cyclopropylmethyl)-1-(4- (trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7- yl)-6-(1,2-dihydroxyethyl)-picolinamide 124

(S)-1-(6-(1-isobutyl-4-(methylsulfonyl)- 2,3,4,5-tetrahydro-1H-benzo-[e][1,4]diazepin-7-yl)pyridin-2- yl)ethane-1,2-diol 125

(2R,3S)-2,3-dihydroxy-3-(6-(1-isobutyl-4-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyridin- 2-yl)propanamide

For the purpose of the present disclosure, the term “alkyl” as used byitself or as part of another group refers to a straight- orbranched-chain aliphatic hydrocarbon containing one to twelve carbonatoms (i.e., C₁₋₁₂ alkyl) or the number of carbon atoms designated(i.e., a C₁ alkyl such as methyl, a C₂ alkyl such as ethyl, a C₃ alkylsuch as propyl or isopropyl, etc.). In embodiment, the alkyl group ischosen from a branched chain C₃₋₁₀ alkyl group. In another embodiment,the alkyl group is chosen from a straight chain C₁₋₆ alkyl group. Inanother embodiment, the alkyl group is chosen from a branched chain C₃₋₆alkyl group. In another embodiment, the alkyl group is chosen from astraight chain C₁₋₄ alkyl group. In another embodiment, the alkyl groupis chosen from a branched chain C₃₋₄ alkyl group. In another embodiment,the alkyl group is chosen from a straight or branched chain C₃₋₄ alkylgroup. Non-limiting exemplary C₁₋₁₀ alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl,hexyl, heptyl, octyl, nonyl, decyl, and the like. Non-limiting exemplaryC₁₋₄ alkyl groups include methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, tert-butyl, and iso-butyl.

For the purpose of the present disclosure, the term “optionallysubstituted alkyl” as used by itself or as part of another group meansthat the alkyl as defined above is either unsubstituted or substitutedwith one, two, or three substituents independently selected from thegroup consisting of nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio,sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl,ureido, guanidino, carboxy, carboxyalkyl, and cycloalkyl. In oneembodiment, the optionally substituted alkyl is substituted with twosubstituents. In another embodiment, the optionally substituted alkyl issubstituted with one substituent. Non-limiting exemplary optionallysubstituted alkyl groups include —CH₂CH₂NO₂, —CH₂CH₂CO₂H, —CH₂CH₂SO₂CH₃,—CH₂CH₂COPh, —CH₂C₆H₁₁, and the like.

For the purpose of the present disclosure, the term “cycloalkyl” as usedby itself or as part of another group refers to saturated and partiallyunsaturated (containing one or two double bonds) cyclic aliphatichydrocarbons containing one to three rings having from three to twelvecarbon atoms (i.e., C₃₋₁₂ cycloalkyl) or the number of carbonsdesignated. In one embodiment, the cycloalkyl group has two rings. Inone embodiment, the cycloalkyl group has one ring. In anotherembodiment, the cycloalkyl group is chosen from a C₃₋₈ cycloalkyl group.In another embodiment, the cycloalkyl group is chosen from a C₃₋₆cycloalkyl group. Non-limiting exemplary cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, cyclopentenyl,cyclohexenyl and the like.

For the purpose of the present disclosure, the term “optionallysubstituted cycloalkyl” as used by itself or as part of another groupmeans that the cycloalkyl as defined above is either unsubstituted orsubstituted with one, two, or three substituents independently selectedfrom the group consisting of halo, nitro, cyano, hydroxy, amino,alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy,aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino,(alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and(heteroaryl)alkyl. In one embodiment, the optionally substitutedcycloalkyl is substituted with two substituents. In another embodiment,the optionally substituted cycloalkyl is substituted with onesubstituent. Non-limiting exemplary optionally substituted cycloalkylgroups include:

For the purpose of the present disclosure, the term “alkenyl” as used byitself or as part of another group refers to an alkyl group as definedabove containing one, two or three carbon-to-carbon double bonds. In oneembodiment, the alkenyl group is chosen from a C₂₋₆ alkenyl group. Inanother embodiment, the alkenyl group is chosen from a C₂ alkenyl group.Non-limiting exemplary alkenyl groups include ethenyl, propenyl,isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

For the purpose of the present disclosure, the term “optionallysubstituted alkenyl” as used herein by itself or as part of anothergroup means the alkenyl as defined above is either unsubstituted orsubstituted with one, two or three substituents independently selectedfrom the group consisting of halo, nitro, cyano, hydroxy, amino,alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy,aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, andheterocyclo.

For the purpose of the present disclosure, the term “alkynyl” as used byitself or as part of another group refers to an alkyl group as definedabove containing one to three carbon-to-carbon triple bonds. In oneembodiment, the alkynyl has one carbon-to-carbon triple bond. In oneembodiment, the alkynyl group is chosen from a C₂₋₆ alkynyl group. Inanother embodiment, the alkynyl group is chosen from a C₂₋₄ alkynylgroup. Non-limiting exemplary alkynyl groups include ethynyl, propynyl,butynyl, 2-butynyl, pentynyl, and hexynyl groups.

For the purpose of the present disclosure, the term “optionallysubstituted alkynyl” as used herein by itself or as part of anothergroup means the alkynyl as defined above is either unsubstituted orsubstituted with one, two or three substituents independently selectedfrom the group consisting of halo, nitro, cyano, hydroxy, amino,alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy,aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, andheterocyclo.

For the purpose of the present disclosure, the term “haloalkyl” as usedby itself or as part of another group refers to an alkyl groupsubstituted by one or more fluorine, chlorine, bromine and/or iodineatoms. In one embodiment, the alkyl group is substituted by one, two, orthree fluorine and/or chlorine atoms. In another embodiment, thehaloalkyl group is chosen from a C₁₋₄ haloalkyl group. Non-limitingexemplary haloalkyl groups include fluoromethyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, andtrichloromethyl groups.

For the purpose of the present disclosure, the term “hydroxyalkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with one or more, e.g., one, two, or three, hydroxy groups.In one embodiment, the hydroxyalkyl group is a monohydroxyalkyl group,i.e., substituted with one hydroxy group. In one embodiment, thehydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with twohydroxy groups, e.g.,

In one embodiment, the hydroxyalkyl group is chosen from a C₁₋₄hydroxyalkyl group. Non-limiting exemplary hydroxyalkyl groups includehydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, suchas 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl,3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl,2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl.

For the purpose of the present disclosure, the terms “(cycloalkyl)alkyl”or “optionally substituted (cycloalkyl)alkyl” as used by themselves oras part of another group refers to an alkyl group substituted with one,two, or three optionally substituted cycloalkyl groups. In oneembodiment, the (cycloalkyl)alkyl group is a C₁₋₄ alkyl substituted withone optionally substituted cycloalkyl group. In one embodiment, the(cycloalkyl)alkyl group is a C₁ or C₂ alkyl substituted with oneoptionally substituted cycloalkyl group. In one embodiment, the(cycloalkyl)alkyl group is a C₁ or C₂ alkyl substituted with onecycloalkyl group. Non-limiting exemplary (cycloalkyl)alkyl groupsinclude:

For the purpose of the present disclosure, the term “alkoxy” as used byitself or as part of another group refers to an optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedalkenyl, or optionally substituted alkynyl attached to a terminal oxygenatom. In one embodiment, the alkoxy group is chosen from a C₁₋₄ alkoxygroup. In another embodiment, the alkoxy group is chosen from a C₁₋₄alkyl attached to a terminal oxygen atom, e.g., methoxy, ethoxy, andtert-butoxy.

For the purpose of the present disclosure, the term “alkylthio” as usedby itself or as part of another group refers to a sulfur atomsubstituted by an optionally substituted alkyl group. In one embodiment,the alkylthio group is chosen from a C₁₋₄ alkylthio group. Non-limitingexemplary alkylthio groups include —SCH₃, and —SCH₂CH₃.

For the purpose of the present disclosure, the term “alkoxyalkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with an alkoxy group. Non-limiting exemplary alkoxyalkylgroups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl,ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl,iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl,tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, andpentyloxymethyl.

For the purpose of the present disclosure, the term “haloalkoxy” as usedby itself or as part of another group refers to a haloalkyl attached toa terminal oxygen atom. Non-limiting exemplary haloalkoxy groups includefluoromethoxy, difluoromethoxy, trifluoromethoxy, and2,2,2-trifluoroethoxy.

For the purpose of the present disclosure, the term “aryl” as used byitself or as part of another group refers to a monocyclic or bicyclicaromatic ring system having from six to fourteen carbon atoms (i.e.,C₆-C₁₄ aryl). Non-limiting exemplary aryl groups include phenyl(abbreviated as “Ph”), naphthyl, phenanthryl, anthracyl, indenyl,azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In oneembodiment, the aryl group is chosen from phenyl or naphthyl.

For the purpose of the present disclosure, the term “optionallysubstituted aryl” as used herein by itself or as part of another groupmeans that the aryl as defined above is either unsubstituted orsubstituted with one to five substituents independently selected fromthe group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino,dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy,heteroaryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido,alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido,guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclo, alkoxy alkyl, (amino)alkyl,hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl,(cycloalkylamino)alkyl, (halo(C₁-C₄)alkoxy)alkyl, and (heteroaryl)alkyl.In one embodiment, the optionally substituted aryl is an optionallysubstituted phenyl. In one embodiment, the optionally substituted phenylhas four substituents. In another embodiment, the optionally substitutedphenyl has three substituents. In another embodiment, the optionallysubstituted phenyl has two substituents. In another embodiment, theoptionally substituted phenyl has one substituent. Non-limitingexemplary substituted aryl groups include 2-methylphenyl,2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl,4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl,3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di-methoxyphenyl,3,5-di-fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl,2-fluoro-3-chlorophenyl, and 3-chloro-4-fluorophenyl. The termoptionally substituted aryl is meant to include groups having fusedoptionally substituted cycloalkyl and fused optionally substitutedheterocyclo rings. Examples include:

For the purpose of the present disclosure, the term “aryloxy” as used byitself or as part of another group refers to an optionally substitutedaryl attached to a terminal oxygen atom. A non-limiting exemplaryaryloxy group is PhO—.

For the purpose of the present disclosure, the term “heteroaryloxy” asused by itself or as part of another group refers to an optionallysubstituted heteroaryl attached to a terminal oxygen atom. Non-limitingexemplary heteroaryloxy groups include:

For the purpose of the present disclosure, the term “aralkyloxy” as usedby itself or as part of another group refers to an aralkyl groupattached to a terminal oxygen atom. A non-limiting exemplary aralkyloxygroup is PhCH₂O—.

For the purpose of the present disclosure, the term “heteroaryl” or“heteroaromatic” refers to monocyclic and bicyclic aromatic ring systemshaving 5 to 14 ring atoms (i.e., C₅-C₁₄ heteroaryl) and 1, 2, 3, or 4heteroatoms independently chosen from oxygen, nitrogen and sulfur. Inone embodiment, the heteroaryl has three heteroatoms. In anotherembodiment, the heteroaryl has two heteroatoms. In another embodiment,the heteroaryl has one heteroatom. In one embodiment, the heteroaryl isa C₅ heteroaryl. In another embodiment, the heteroaryl is a C₆heteroaryl. Non-limiting exemplary heteroaryl groups include thienyl,benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl,pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl,2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl,purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl,furazanyl, and phenoxazinyl. In one embodiment, the heteroaryl is chosenfrom thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl(e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g.,1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g.,pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g.,pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g.,thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g.,isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g.,oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g.,isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl). The term “heteroaryl”is also meant to include possible N-oxides. Exemplary N-oxides includepyridyl N-oxide and the like.

For the purpose of the present disclosure, the term “optionallysubstituted heteroaryl” as used by itself or as part of another groupmeans that the heteroaryl as defined above is either unsubstituted orsubstituted with one to four substituents, e.g., one or twosubstituents, independently selected from the group consisting of halo,nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl,hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio,carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl,arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl,(dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl,(heterocyclo)alkyl, and (heteroaryl)alkyl. In one embodiment, theoptionally substituted heteroaryl has one substituent. In oneembodiment, the optionally substituted is an optionally substitutedpyridyl, i.e., 2-, 3-, or 4-pyridyl. Any available carbon or nitrogenatom can be substituted. In another embodiment, the optionallysubstituted heteroaryl is an optionally substituted indole.

For the purpose of the present disclosure, the term “heterocycle” or“heterocyclo” as used by itself or as part of another group refers tosaturated and partially unsaturated (e.g., containing one or two doublebonds) cyclic groups containing one, two, or three rings having fromthree to fourteen ring members (i.e., a 3- to 14-membered heterocyclo)and at least one heteroatom. Each heteroatom is independently selectedfrom the group consisting of oxygen, sulfur, including sulfoxide andsulfone, and/or nitrogen atoms, which can be quaternized. The term“heterocyclo” is meant to include cyclic ureido groups such as2-imidazolidinone and cyclic amide groups such as β-lactam, γ-lactam,δ-lactam and ε-lactam. The term “heterocyclo” is also meant to includegroups having fused optionally substituted aryl groups, e.g., indolinyl.In one embodiment, the heterocyclo group is chosen from a 5- or6-membered cyclic group containing one ring and one or two oxygen and/ornitrogen atoms. The heterocyclo can be optionally linked to the rest ofthe molecule through a carbon or nitrogen atom. Non-limiting exemplaryheterocyclo groups include 2-oxopyrrolidin-3-yl, 2-imidazolidinone,piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and indolinyl.

For the purpose of the present disclosure, the term “optionallysubstituted heterocyclo” as used herein by itself or part of anothergroup means the heterocyclo as defined above is either unsubstituted orsubstituted with one to four substituents independently selected fromthe group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino,dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy,aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino,(alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and(heteroaryl)alkyl. Substitution may occur on any available carbon ornitrogen atom, and may form a spirocycle. Non-limiting exemplaryoptionally substituted heterocyclo groups include:

For the purpose of the present disclosure, the term “amino” as used byitself or as part of another group refers to —NH₂.

For the purpose of the present disclosure, the term “alkylamino” as usedby itself or as part of another group refers to —NHR¹⁵, wherein R¹⁵ isalkyl.

For the purpose of the present disclosure, the term “dialkylamino” asused by itself or as part of another group refers to —NR^(16a)R^(16b),wherein R^(16a) and R^(16b) are each independently alkyl or R^(16a) andR^(16b) are taken together to form a 3- to 8-membered optionallysubstituted heterocyclo.

For the purpose of the present disclosure, the term “hydroxyalkylamino”as used by itself or as part of another group refers to —NHR¹⁷, whereinR¹⁷ is hydroxyalkyl.

For the purpose of the present disclosure, the term “cycloalkylamino” asused by itself or as part of another group refers to —NR^(19a)R^(19b),wherein R^(19a) is optionally substituted cycloalkyl and R^(19b) ishydrogen or alkyl.

For the purpose of the present disclosure, the term “(amino)alkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with an amino group. Non-limiting exemplary amino alkylgroups include —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂NH₂ and the like.

For the purpose of the present disclosure, the term “(alkylamino)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with an alkylamino group. A non-limiting exemplary(alkylamino)alkyl group is —CH₂CH₂N(H)CH₃.

For the purpose of the present disclosure, the term“(dialkylamino)alkyl” as used by itself or as part of another grouprefers to an alkyl group substituted by a dialkylamino group.Non-limiting exemplary (dialkylamino)alkyl groups include —CH₂N(CH₃)₂and —CH₂CH₂N(CH₃)₂.

For the purpose of the present disclosure, the term“(cycloalkylamino)alkyl” as used by itself or as part of another grouprefers to an alkyl group substituted by a cycloalkylamino group.Non-limiting exemplary (cycloalkylamino)alkyl groups includeCH₂N(H)cyclopropyl, —CH₂N(H)cyclobutyl, and —CH₂N(H)cyclohexyl.

For the purpose of the present disclosure, the term“(halo(C₁-C₄)alkoxy)alkyl” as used by itself or as part of another grouprefers to an alkyl group substituted by a C₁-C₄ haloalkoxy group.Non-limiting exemplary (halo(C₁-C₄)alkoxy)alkyl groups include—CH₂OCH₂CF₃ and CH₂OCF₃.

For the purpose of the present disclosure, the term “(cyano)alkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with one or more cyano, e.g., —CN, groups. Non-limitingexemplary (cyano)alkyl groups include —CH₂CH₂CN, —CH₂CH₂CH₂CN, and—CH₂CH₂CH₂CH₂CN.

For the purpose of the present disclosure, the term “carboxamido” asused by itself or as part of another group refers to a radical offormula —C(═O)NR^(24a)R^(24b) wherein R^(24a) and R^(24b) are eachindependently hydrogen, optionally substituted alkyl, optionallysubstituted aralkyl, optionally substituted aryl, or optionallysubstituted heteroaryl, or R^(24a) and R^(24b) taken together with thenitrogen to which they are attached from a 3- to 8-membered heterocyclogroup. In one embodiment, R^(24a) and R^(24b) are each independentlyhydrogen or optionally substituted alkyl. Non-limiting exemplarycarboxamido groups include —CONH₂, —CON(H)CH₃, CON(CH₃)₂, and CON(H)Ph.

For the purpose of the present disclosure, the term “sulfonamido” asused by itself or as part of another group refers to a radical of theformula —SO₂NR^(23a)R^(23b), wherein R^(23a) and R^(23b) are eachindependently hydrogen, optionally substituted alkyl, or optionallysubstituted aryl, or R^(23a) and R^(23b) taken together with thenitrogen to which they are attached from a 3- to 8-membered heterocyclogroup. Non-limiting exemplary sulfonamido groups include —SO₂NH₂,—SO₂N(H)CH₃, and —SO₂N(H)Ph.

For the purpose of the present disclosure, the term “alkylcarbonyl” asused by itself or as part of another group refers to a carbonyl group,i.e., —C(═O)—, substituted by an alkyl group. A non-limiting exemplaryalkylcarbonyl group is —COCH₃.

For the purpose of the present disclosure, the term “arylcarbonyl” asused by itself or as part of another group refers to a carbonyl group,i.e., —C(═O)—, substituted by an optionally substituted aryl group. Anon-limiting exemplary arylcarbonyl group is —COPh.

For the purpose of the present disclosure, the term “alkylsulfonyl” asused by itself or as part of another group refers to a sulfonyl group,i.e., —SO₂—, substituted by any of the above-mentioned optionallysubstituted alkyl groups. A non-limiting exemplary alkylsulfonyl groupis —SO₂CH₃.

For the purpose of the present disclosure, the term “arylsulfonyl” asused by itself or as part of another group refers to a sulfonyl group,i.e., —SO₂—, substituted by any of the above-mentioned optionallysubstituted aryl groups. A non-limiting exemplary arylsulfonyl group is—SO₂Ph.

For the purpose of the present disclosure, the term “mercaptoalkyl” asused by itself or as part of another group refers to any of theabove-mentioned alkyl groups substituted by a SH group.

For the purpose of the present disclosure, the term “carboxy” as used byitself or as part of another group refers to a radical of the formula—COOH.

For the purpose of the present disclosure, the term “carboxyalkyl” asused by itself or as part of another group refers to any of theabove-mentioned alkyl groups substituted with a —COOH. A non-limitingexemplary carboxyalkyl group is —CH₂CO₂H.

For the purpose of the present disclosure, the terms “aralkyl” or“arylalkyl” or “optionally substituted aralkyl” as used by themselves oras part of another group refers to an alkyl group substituted with one,two, or three optionally substituted aryl groups. In one embodiment, theoptionally substituted aralkyl group is a C₁₋₄ alkyl substituted withone optionally substituted aryl group. In one embodiment, the optionallysubstituted aralkyl group is a C₁ or C₂ alkyl substituted with oneoptionally substituted aryl group. In one embodiment, the optionallysubstituted aralkyl group is a C₁ or C₂ alkyl substituted with oneoptionally substituted phenyl group. Non-limiting exemplary optionallysubstituted aralkyl groups include benzyl, phenethyl, —CHPh₂,—CH₂(4-F-Ph), —CH₂(4-Me-Ph), —CH₂(4-CF₃-Ph), and —CH(4-F-Ph)₂.

For the purpose of the present disclosure, the term “ureido” as used byitself or as part of another group refers to a radical of the formula—NR^(22a)—C(═O)—NR^(22b)R^(22c), wherein R^(22a) is hydrogen, alkyl, oroptionally substituted aryl, and R^(22b) and R^(22c) are eachindependently hydrogen, alkyl, or optionally substituted aryl, orR^(22b) and R^(22c) taken together with the nitrogen to which they areattached form a 4- to 8-membered heterocyclo group. Non-limitingexemplary ureido groups include —NH—C(═O)—NH₂ and —NH—C(═O)—NHCH₃.

For the purpose of the present disclosure, the term “guanidino” as usedby itself or as part of another group refers to a radical of the formula—NR^(25a)—C(═NR²⁶)—NR^(25b)R^(25c), wherein R^(25a), R^(25b), andR^(25c) are each independently hydrogen, alkyl, or optionallysubstituted aryl, and R²⁶ is hydrogen, alkyl, cyano, alkylsulfonyl,alkylcarbonyl, carboxamido, or sulfonamido. Non-limiting exemplaryguanidino groups include —NH—C(═NH)—NH₂, —NH—C(═NCN)—NH₂,—NH—C(═NH)—NHCH₃ and the like.

For the purpose of the present disclosure, the terms “(heteroaryl)alkyl”or “optionally substituted (heteroaryl)alkyl” as used by themselves oras part of another group refers to an alkyl group substituted with one,two, or three optionally substituted heteroaryl groups. In oneembodiment, the (heteroaryl)alkyl group is a C₁₋₄ alkyl substituted withone optionally substituted heteroaryl group. In one embodiment, the(heteroaryl)alkyl is a C₁ or C₂ alkyl substituted with one optionallysubstituted heteroaryl group. Non-limiting exemplary (heteroaryl)alkylgroups include:

For the purpose of the present disclosure, the term “heteroalkyl” asused by itself or part of another group refers to a stable straight orbranched chain hydrocarbon radical containing 1 to 10 carbon atoms andat least two heteroatoms, which can be the same or different, selectedfrom O, N, or S, wherein: 1) the nitrogen atom(s) and sulfur atom(s) canoptionally be oxidized; and/or 2) the nitrogen atom(s) can optionally bequaternized. The heteroatoms can be placed at any interior position orterminal position of the heteroalkyl group, or at a position at whichthe heteroalkyl group is attached to the remainder of the molecule. Inone embodiment, the heteroalkyl group contains two oxygen atoms. Inanother embodiment, the heteroalkyl group contains two nitrogen atoms.In other embodiment, the heteroalkyl group contains one nitrogen atomand one oxygen atom. Non-limiting exemplary heteroalkyl groups include:—CH₂N(H)CH₂CH₂N(CH₃)₂; —CH₂N(CH₃)CH₂CH₂N(CH₃)₂;—CH₂N(H)CH₂CH₂CH₂N(CH₃)₂; —CH₂N(H)CH₂CH₂OH; —CH₂N(CH₃)CH₂CH₂OH;—CH₂OCH₂CH₂OCH₃, —OCH₂CH₂OCH₂CH₂OCH₃; —CH₂NHCH₂CH₂OCH₂; —OCH₂CH₂NH₂; and—NHCH₂CH₂N(H)CH₃.

For the purpose of the present disclosure, the term “(heterocyclo)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with one optionally substituted heterocyclo group, andoptionally one hydroxy group. In one embodiment, the (heterocyclo)alkylis a C₁₋₄ alkyl substituted with one optionally substituted heterocyclogroup and one hydroxy group. In another embodiment, the(heterocyclo)alkyl is a C₁₋₄ alkyl substituted with one optionallysubstituted heterocyclo group. Non-limiting exemplary (heterocyclo)alkylgroups include:

For the purpose of the present disclosure, the term “(carboxamido)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with one carboxamido group, and optionally one heterocyclo,amino, alkylamino, or dialkylamino group. In one embodiment, the(carboxamido)alkyl is a C₁₋₄ alkyl substituted with one carboxamidogroup, and optionally one heterocyclo, amino, alkylamino, ordialkylamino group. In another embodiment, the (carboxamido)alkyl is aC₁₋₄ alkyl substituted with one carboxamido group and one heterocyclo,amino, alkylamino, or dialkylamino group. In another embodiment, the(carboxamido)alkyl is a C₁₋₄ alkyl substituted with one carboxamidogroup. Non-limiting exemplary (carboxamido)alkyl groups include—CH₂CONH₂, —C(H)CH₃—CONH₂, —CH₂CON(H)CH₃,

The present disclosure encompasses any of the Compounds of theDisclosure being isotopically-labelled (i.e., radiolabeled) by havingone or more atoms replaced by an atom having a different atomic mass ormass number. Examples of isotopes that can be incorporated into thedisclosed compounds include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively, e.g.,³H, ¹¹C, and ¹⁴C. Isotopically-labeled Compounds of the Disclosure canbe prepared by methods known in the art.

The present disclosure encompasses ³H, ¹¹C, or ¹⁴C radiolabeledCompounds of the Disclosure and the use of any such compounds asradioligands for their ability to bind to the sodium channel. Forexample, one use of the labeled compounds of the present disclosure isthe characterization of specific receptor binding. Another use of alabeled Compound of the Disclosure is an alternative to animal testingfor the evaluation of structure-activity relationships. For example, thereceptor assay can be performed at a fixed concentration of a labeledCompound of the Disclosure and at increasing concentrations of a testcompound in a competition assay. For example, a tritiated Compound ofthe Disclosure can be prepared by introducing tritium into theparticular compound, for example, by catalytic dehalogenation withtritium. This method may include reacting a suitably halogen-substitutedprecursor of the compound with tritium gas in the presence of a suitablecatalyst, for example, Pd/C, in the presence or absence of a base. Othersuitable methods for preparing tritiated compounds can be found inFiler, Isotopes in the Physical and Biomedical Sciences, Vol. 1, LabeledCompounds (Part A), Chapter 6 (1987). ¹⁴C-labeled compounds can beprepared by employing starting materials having a ¹⁴C carbon.

Some of the Compounds of the Disclosure may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms. The present disclosure is meant toencompass the use of all such possible forms, as well as their racemicand resolved forms and mixtures thereof. The individual enantiomers canbe separated according to methods known in the art in view of thepresent disclosure. When the compounds described herein contain olefinicdouble bonds or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that they include both E and Zgeometric isomers. All tautomers are intended to be encompassed by thepresent disclosure as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The terms “a” and “an” refer to one or more.

The term “treat,” “treating” or “treatment” is meant to encompassadministering to a subject a compound of the present disclosure for thepurposes of amelioration or cure, including preemptive and palliativetreatment. In one embodiment, the term “treat,” “treating” or“treatment” is meant to encompass administering to a subject a compoundof the present disclosure for the purposes of amelioration or cure.

The term “about,” as used herein in connection with a measured quantity,refers to the normal variations in that measured quantity, as expectedby the skilled artisan making the measurement and exercising a level ofcare commensurate with the objective of measurement and the precision ofthe measuring equipment.

The present disclosure encompasses the preparation and use of salts ofthe Compounds of the Disclosure, including non-toxic pharmaceuticallyacceptable salts. Examples of pharmaceutically acceptable addition saltsinclude inorganic and organic acid addition salts and basic salts. Thepharmaceutically acceptable salts include, but are not limited to, metalsalts such as sodium salt, potassium salt, cesium salt and the like;alkaline earth metals such as calcium salt, magnesium salt and the like;organic amine salts such as triethylamine salt, pyridine salt, picolinesalt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt and the like; inorganic acid saltssuch as hydrochloride, hydrobromide, phosphate, sulphate and the like;organic acid salts such as citrate, lactate, tartrate, maleate,fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate,oxalate, formate and the like; sulfonates such as methanesulfonate,benzenesulfonate, p-toluenesulfonate and the like; and amino acid saltssuch as arginate, asparginate, glutamate and the like.

Acid addition salts can be formed by mixing a solution of the particularCompound of the Disclosure with a solution of a pharmaceuticallyacceptable non-toxic acid such as hydrochloric acid, fumaric acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or thelike. Basic salts can be formed by mixing a solution of the compound ofthe present disclosure with a solution of a pharmaceutically acceptablenon-toxic base such as sodium hydroxide, potassium hydroxide, cholinehydroxide, sodium carbonate and the like.

The present disclosure encompasses the preparation and use of solvatesof Compounds of the Disclosure. Solvates typically do not significantlyalter the physiological activity or toxicity of the compounds, and assuch may function as pharmacological equivalents. The term “solvate” asused herein is a combination, physical association and/or solvation of acompound of the present disclosure with a solvent molecule such as, e.g.a disolvate, monosolvate or hemisolvate, where the ratio of solventmolecule to compound of the present disclosure is about 2:1, about 1:1or about 1:2, respectively. This physical association involves varyingdegrees of ionic and covalent bonding, including hydrogen bonding. Incertain instances, the solvate can be isolated, such as when one or moresolvent molecules are incorporated into the crystal lattice of acrystalline solid. Thus, “solvate” encompasses both solution-phase andisolatable solvates. Compounds of the Disclosure can be present assolvated forms with a pharmaceutically acceptable solvent, such aswater, methanol, ethanol, and the like, and it is intended that thedisclosure includes both solvated and unsolvated forms of Compounds ofthe Disclosure. One type of solvate is a hydrate. A “hydrate” relates toa particular subgroup of solvates where the solvent molecule is water.Solvates typically can function as pharmacological equivalents.Preparation of solvates is known in the art. See, for example, M. Cairaet al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes thepreparation of solvates of fluconazole with ethyl acetate and withwater. Similar preparation of solvates, hemisolvates, hydrates, and thelike are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech.,5(1):Article 12 (2004), and A. L. Bingham et al., Chem. Commun. 603-604(2001). A typical, non-limiting, process of preparing a solvate wouldinvolve dissolving a Compound of the Disclosure in a desired solvent(organic, water, or a mixture thereof) at temperatures above 20° C. toabout 25° C., then cooling the solution at a rate sufficient to formcrystals, and isolating the crystals by known methods, e.g., filtration.Analytical techniques such as infrared spectroscopy can be used toconfirm the presence of the solvent in a crystal of the solvate.

Since Compounds of the Disclosure are blockers of sodium (Na⁺) channels,a number of diseases and conditions mediated by sodium ion influx can betreated by employing these compounds. The present disclosure is thusdirected generally to a method for treating a disorder or alleviatingsymptoms thereof, wherein the disorder is responsive to the blockade ofsodium channels in an animal suffering from, or at risk of sufferingfrom, said disorder, said method comprising administering to the animalan effective amount of one or more Compounds of the Disclosure.

The present disclosure is further directed to a method of modulatingsodium channels in an animal in need thereof, said method comprisingadministering to the animal a modulating-effective amount of at leastone Compound of the Disclosure.

More specifically, the present disclosure provides a method of treatingstroke, neuronal damage resulting from head trauma, epilepsy, neuronalloss following global and focal ischemia, pain (e.g., acute pain,chronic pain, which includes but is not limited to neuropathic pain,postoperative pain, and inflammatory pain, or surgical pain), aneurodegenerative disorder (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS), or Parkinson's disease), migraine, manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or alleviating symptoms thereof, or providing localanesthesia. In one embodiment, the disclosure provides a method oftreating pain. In another embodiment, the type of pain is chronic pain.In another embodiment, the type of pain is neuropathic pain. In anotherembodiment, the type of pain is postoperative pain. In anotherembodiment, the type of pain is inflammatory pain. In anotherembodiment, the type of pain is surgical pain. In another embodiment,the type of pain is acute pain. In another embodiment, the treatment ofpain (e.g., chronic pain, such as neuropathic pain, postoperative pain,or inflammatory pain, acute pain or surgical pain) is preemptive. Inanother embodiment, the treatment of pain is palliative. In eachinstance, such method of treatment requires administering to an animalin need of such treatment an amount of a Compound of the Disclosure thatis therapeutically effective in achieving said treatment. In oneembodiment, the amount of such compound is the amount that is effectiveto block sodium channels in vitro. In one embodiment, the amount of suchcompound is the amount that is effective to block sodium channels invivo.

Chronic pain includes, but is not limited to, inflammatory pain,postoperative pain, cancer pain, osteoarthritis pain associated withmetastatic cancer, trigeminal neuralgia, acute herpetic and postherpeticneuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion,occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout,phantom limb pain, burn pain, and other forms of neuralgia, neuropathic,and idiopathic pain syndromes.

Chronic somatic pain generally results from inflammatory responses totissue injury such as nerve entrapment, surgical procedures, cancer orarthritis (Brower, Nature Biotechnology 18:387-391 (2000)).

The inflammatory process is a complex series of biochemical and cellularevents activated in response to tissue injury or the presence of foreignsubstances (Levine, Inflammatory Pain, In: Textbook of Pain, Wall andMelzack eds., 3^(rd) ed., 1994). Inflammation often occurs at the siteof injured tissue, or foreign material, and contributes to the processof tissue repair and healing. The cardinal signs of inflammation includeerythema (redness), heat, edema (swelling), pain and loss of function(ibid.). The majority of patients with inflammatory pain do notexperience pain continually, but rather experience enhanced pain whenthe inflamed site is moved or touched. Inflammatory pain includes, butis not limited to, that associated with osteoarthritis and rheumatoidarthritis.

Chronic neuropathic pain is a heterogeneous disease state with anunclear etiology. In chronic neuropathic pain, the pain can be mediatedby multiple mechanisms. This type of pain generally arises from injuryto the peripheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. Chronic pain is differentfrom acute pain in that patients suffer the abnormal pain sensationsthat can be described as spontaneous pain, continuous superficialburning and/or deep aching pain. The pain can be evoked by heat-, cold-,and mechano-hyperalgesia or by heat-, cold-, or mechano-allodynia.

Neuropathic pain can be caused by injury or infection of peripheralsensory nerves. It includes, but is not limited to, pain from peripheralnerve trauma, herpes virus infection, diabetes mellitus, causalgia,plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathicpain is also caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiencies. Stroke (spinal or brain) and spinal cord injury can alsoinduce neuropathic pain. Cancer-related neuropathic pain results fromtumor growth compression of adjacent nerves, brain, or spinal cord. Inaddition, cancer treatments, including chemotherapy and radiationtherapy, can also cause nerve injury. Neuropathic pain includes but isnot limited to pain caused by nerve injury such as, for example, thepain from which diabetics suffer.

The present disclosure is also directed to the use of a Compound of theDisclosure in the manufacture of a medicament for treating a disorder oralleviating symptoms thereof in an animal suffering from said disorder,wherein said disorder is responsive to the blockade of sodium channels(e.g., any of the disorders listed above).

General Synthesis of Compounds

Compounds of Formula I can be prepared by using conventional organicsynthesis in view of this disclosure, or by the illustrative methodsshown in the General Schemes below.

In General Scheme 1, Compound A (wherein PG is a protecting group and Xis a suitable leaving group such as halide, triflate, tosylate,mesylate, etc.) is converted to Compound C by reaction with Compound Bin the presence of a suitable catalyst such as Pd(dppf)Cl₂ and asuitable base such as KOAc in a suitable solvent such as dioxane.Compound C is converted to Compound E by reaction with Compound D in thepresence of a suitable catalyst such as Pd(PPh₃)₂Cl₂ and a suitable basesuch as Na₂CO₃ in a suitable solvent such as DME.

In General Scheme 2, Compound E from General Scheme 1 is converted toCompound G by appropriate deprotection techniques known to one skilledin the art (e.g. Wuts, P. G. M.; Greene, T. W., “Greene's ProtectiveGroups in Organic Synthesis”, 4th Ed., J. Wiley & Sons, NY, 2007).Compound G is converted to Compound I by alkylation with a suitablealkyl halide, triflate, tosylate, mesylate, etc. in the presence of asuitable base such as DIPEA in a suitable solvent such as ACN or byreductive ammination with the appropriate aldehyde/ketone in thepresence of a suitable reducing agent such as NaBH(OAc)₃ in a suitablesolvent such as DCM. Compound G is converted to Compound J by reactionwith the appropriate sulfonyl chloride in the presence of a suitablebase such as TEA in a suitable solvent such as DCM.

In General Scheme 3, Compound K is converted to Compound M by reactionwith Compound L in the presence of a suitable catalyst such asPd(dppf)Cl₂ and a suitable base such as Na₂CO₃ in a suitable solventsuch as aq. dioxane. Compound M can be converted to Compound N byreaction with a suitable reagent such as OsO₄ in a suitable solvent suchas aq. acetone, or with a suitable chiral reagent such as AD-mix alphaor beta in a suitable solvent such as aq. t-BuOH.

Testing of Compounds

Compounds of the Disclosure were assessed by sodium mobilization and/orelectrophysiological (EP) assays for sodium channel blocker activity.One aspect of the present disclosure is based on the use of theCompounds of the Disclosure as sodium channel blockers. Based upon thisproperty, Compounds of the Disclosure are considered useful in treatinga condition or disorder responsive to the blockade of sodium ionchannels, e.g., stroke, neuronal damage resulting from head trauma,epilepsy, seizures, general epilepsy with febrile seizures, severemyoclonic epilepsy in infancy, neuronal loss following global and focalischemia, migraine, familial primary erythromelalgia, paroxysmal extremepain disorder, cerebellar atrophy, ataxia, dystonia, tremor, mentalretardation, autism, a neurodegenerative disorder (e.g., Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease),manic depression, tinnitus, myotonia, a movement disorder, cardiacarrhythmia, or providing local anesthesia. Compounds of the Disclosureare also expected to be effective in treating pain, e.g., acute pain,chronic pain, which includes but is not limited to, neuropathic pain,postoperative pain, and inflammatory pain, or surgical pain.

More specifically, the present disclosure is directed to Compounds ofthe Disclosure that are blockers of sodium channels. According to thepresent disclosure, those compounds having useful sodium channelblocking properties exhibit an IC₅₀ for Na_(v)1.1, Na_(v)1.2, Na_(v)1.3,Na_(v)1.4, Na_(v)1.5, Na_(v)1.6, Na_(v)1.7, Na_(v)1.8, and/or Na_(v)1.9of about 100 μM or less, e.g., about 50 μM or less, about 25 μM or less,about 10 μM or less, about 5 μM or less, or about 1 μM or less, insodium mobilization and/or electrophysiological assays. In certainembodiments, Compounds of the Disclosure exhibit an IC₅₀ for Na_(v)1.7of 100 μM or less, about 50 μM or less, about 25 μM or less, about 10 μMor less, about 5 μM or less, about 1 μM or less, about 0.5 μM or less,about 0.1 μM or less, about 0.05 μM or less, or about 0.01 μM or less.Compounds of the Disclosure can be tested for their Na⁺ channel blockingactivity using methods known in the art and by the followingfluorescence imaging and electrophysiological in vitro assays and/or invivo assays.

In one embodiment, Compounds of the Disclosure demonstrate substantiallyno penetration across the CNS blood-brain barrier in a mammal Suchcompounds are referred to as “peripherally restricted” as a means todesignate their PNS versus CNS tissue selectivity.

In one embodiment, the PNS:CNS concentration ratio of a peripherallyrestricted Compound of the Disclosure is about 5:1, about 10:1, about20:1, about 30:1; about 50:1; about 100:1, about 250:1, about 500:1,about 1000:1, about 5,000:1, about 10,000:1, or more. Compounds of theDisclosure can be tested for their ability to penetrate the centralnervous system using in vitro and in vivo methods known in the art.

In Vitro Assay Protocols

FLIPR® Assays

Recombinant Na_(v)1.7 Cell Line:

In vitro assays were performed in a recombinant cell line expressingcDNA encoding the alpha subunit (Na_(v)1.7, SCN9a, PN1, NE) of humanNa_(v)1.7 (Accession No. NM_002977). The cell line was provided byinvestigators at Yale University (Cummins et al, J. Neurosci. 18(23):9607-9619 (1998)). For dominant selection of the Na_(v)1.7-expressingclones, the expression plasmid co-expressed the neomycin resistancegene. The cell line was constructed in the human embryonic kidney cellline, HEK293, under the influence of the CMV major late promoter, andstable clones were selected using limiting dilution cloning andantibiotic selection using the neomycin analogue, G418. Recombinant betaand gamma subunits were not introduced into this cell line. Additionalcell lines expressing recombinant Na_(v)1.7 cloned from other speciescan also be used, alone or in combination with various beta subunits,gamma subunits or chaperones.

Non-Recombinant Cell Lines Expressing Native Na_(v)1.7:

Alternatively, in vitro assays can be performed in a cell lineexpressing native, non-recombinant Na_(v)1.7, such as the ND7 mouseneuroblastoma X rat dorsal root ganglion (DRG) hybrid cell line ND7/23,available from the European Cell Culture Collection (Cat. No. 92090903,Salisbury, Wiltshire, United Kingdom). The assays can also be performedin other cell lines expressing native, non-recombinant Na_(v)1.7, fromvarious species, or in cultures of fresh or preserved sensory neurons,such as dorsal root ganglion (DRG) cells, isolated from various species.Primary screens or counter-screens of other voltage-gated sodiumchannels can also be performed, and the cell lines can be constructedusing methods known in the art, purchased from collaborators orcommercial establishments, and they can express either recombinant ornative channels. The primary counter-screen is for one of the centralneuronal sodium channels, Na_(v)1.2 (rBIIa), expressed in HEK293 hostcells (Ilyin et al., Br. J. Pharmacol. 144:801-812 (2005)).Pharmacological profiling for these counter-screens is carried out underconditions similar to the primary or alternative Na_(v)1.7 assaysdescribed below.

Cell Maintenance:

Unless otherwise noted, cell culture reagents were purchased fromMediatech of Herndon, Va. The recombinant Na_(v)1.7/HEK293 cells wereroutinely cultured in growth medium consisting of Dulbecco's minimumessential medium containing 10% fetal bovine serum (FBS, Hyclone, ThermoFisher Scientific, Logan, Utah), 100 U/mL penicillin, 100 μg/mLstreptomycin, 2-4 mM L-glutamine, and 500 mg/mL G418. For natural,non-recombinant cell lines, the selective antibiotic was omitted, andadditional media formulations can be applied as needed.

Assay Buffer:

The assay buffer was formulated by removing 120 mL from a 1 L bottle offresh, sterile dH₂O (Mediatech, Herndon, Va.) and adding 100 mL of10×HBSS that does not contain Ca⁺⁺ or Mg⁺⁺ (Gibco, Invitrogen, GrandIsland, N.Y.) followed by 20 mL of 1.0 M Hepes, pH 7.3 (FisherScientific, BP299-100). The final buffer consisted of 20 mM Hepes, pH7.3, 1.261 mM CaCl₂, 0.493 mM MgCl₂, 0.407 mM Mg(SO)₄, 5.33 mM KCl,0.441 mM KH₂PO₄, 137 mM NaCl, 0.336 mM Na₂HPO₄ and 0.556 mM D-glucose(Hanks et al., Proc. Soc. Exp. Biol. Med. 71:196 (1949)), and the simpleformulation was typically the basic buffer throughout the assay (i.e.,all wash and addition steps).

CoroNa™ Green AM Na⁺ Dye for Primary Fluorescence Assay:

The fluorescence indicator used in the primary fluorescence assay wasthe cell permeant version of CoroNa™ Green (Invitrogen, MolecularProbes, Eugene, Oreg.), a dye that emits light in the fluorescence range(Harootunian et al., J. Biol. Chem. 264(32):19458-19467 (1989)). Theintensity of this emission, but not the wavelength range, is increasedwhen the dye is exposed to Na⁺ ions, which it can bind with partialselectivity. Cells expressing Na_(v)1.7 or other sodium channels wereloaded with the CoroNa™ Green dye immediately in advance of thefluorescence assay, and then, after agonist stimulation, themobilization of Na⁺ ions was detected as the Na⁺ ions flowed from theextracellular fluid into the cytoplasm through the activated sodiumchannel pores. The dye was stored in the dark as a lyophilized powder,and then an aliquot was dissolved immediately before the cell loadingprocedure, according to the instructions of the manufacturer, to a stockconcentration of 10 mM in DMSO. It was then diluted in the assay bufferto a 4× concentrated working solution, so that the final concentrationof dye in the cell loading buffer was 5 μM.

Membrane Potential Dye for Alternative Fluorescence Assays:

A fluorescence indicator that can be used in alternative fluorescenceassays is the blue version membrane potential dye (MDS, MolecularDevices, Sunnyvale, Calif.), a dye that detects changes in moleculesfollowing a change in membrane potential. An increase in fluorescence isexpected if agonist stimulation provokes a change in membrane potential.Cells expressing Na_(v)1.7 or other sodium channels are incubated withthe membrane potential dye 30-60 minutes before the fluorescence assay.In the case of the KCl pre-stimulation version of the assay, the dye andall other components are washed out immediately before the assay, andthe dye is then replaced. In the version lacking KCl pre-stimulation,the dye remains on the cells and is not washed out or replaced. The dyeis stored in the dark as a lyophilized powder, and then an aliquotdissolved in assay buffer to form a 20×-concentrated stock solution thatcan be used for several weeks.

Agonists:

In the fluorescence assays, two agonists were used in combination,namely 1) veratridine; and 2) the venom from the yellow scorpion,Leiurus quinquestriatus hebraeus. Veratridine is an alkaloid smallmolecule that facilitates the capture of channel openings by inhibitinginactivation, and the scorpion venom is a natural preparation thatincludes peptide toxins selective for different subsets of voltage-gatedsodium channels. These scorpion toxins inhibit the fast inactivation oftheir cognate target channels. Stock solutions of the agonists wereprepared to 40 mM in DMSO (veratridine) and 1 mg/mL in dH₂O (scorpionvenom), and then diluted to make a 4× or 2× stock (depending on theparticular assay) in assay buffer, the final concentration being 100 μM(veratridine) and 10 μg/mL (scorpion venom). Both of the agonists werepurchased from Sigma Aldrich, St. Louis, Mo.

Test Compounds:

Test compounds were dissolved in DMSO to yield 10 mM stock solutions.The stock solutions were further diluted using DMSO in 1:3 serialdilution steps with 10 points (10,000 μM, 3.333 μM, 1.111 μM, 370 μM,123 μM, 41 μM, 14 μM, 4.6 μM, 1.5 μM and 0.5 μM). The stock solutionswere further diluted in assay buffer (1:125) as 4× stock serialdilutions with a DMSO concentration of 0.8% (final [DMSO], in the assay,from the compounds component=0.2%), so that the compounds' finalconcentrations in the assay were 20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μMand 0.08 μM, 0.03 μM, 0.01 μM, 0.003 μM and 0.001 μM. If a particulartest article appeared to be especially potent, then the concentrationcurve was adjusted, e.g., to 10-fold lower concentrations, in order toperform the dose-response in a more relevant concentration range.Compound dilutions were added during the dye-loading and pre-stimulationstep, and then again during the fluorescence assay, early in the kineticread. Compound dilutions were added in duplicate rows across the middle80 wells of the 96-well plate, whereas the fully stimulated and thefully inhibited controls (positive and negative) were located in the top4 side wells and the bottom 4 side wells, respectively, on the left andright sides of the assay plate.

Data Analysis:

The data were analyzed according to methods known to those skilled inthe art or using the GraphPad® Prism Program, version 4.0 or higher(available from GraphPad Software, San Diego, Calif.) to determine theIC₅₀ value for the test article. At least one standard referencecompound was evaluated during each experiment.

FLIPR® or FLIPR^(TETRA)® Sodium Dye Assay with KCl and Test ArticlePre-Incubation:

Cells were prepared by plating the recombinant HEK293 cells or otherhost cells expressing either recombinant or non-recombinant, native,Na_(v)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of 40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately fewer cells andless media. The plate was then incubated in growth media, with orwithout selective antibiotic, overnight at 37° C. at 5% CO₂, 95%humidity, in preparation for the assay. For counter-screens of othervoltage-gated sodium channels, the procedure was very similar, thoughoptimal densities of cells, media and subsequent assay components can befine-tuned for the particular cell line or isoform.

The next day, at the start of the assay, the media was flicked from thecells and the wells were washed once with 50 assay buffer (1× Hank'sbalanced salt solution without sodium bicarbonate or phenol red, 20 mMHepes, pH 7.3) and then pre-incubated with the test articles, CoroNa™Green AM sodium dye (for cell loading) and KCl for re-polarization andsynchronization of the channels in the entire population of cells. Forthis dye-loading and pre-stimulation step, the components were added asfollows, immediately after the wash step: 1) first, the compounddilutions and controls were added as 4× concentrates in assay buffer at50 μL/well; 2) CoroNa™ Green AM dye was diluted from the stock solutionto 20 μM in assay buffer (4× concentrate) and added to the plate at 50μL/well; and 3) finally, a solution of 180 mM KCl (2×) was prepared bydiluting a 2M stock solution into assay buffer and the solution wasadded to the cells at 100 μl/well. The cells were incubated at 25° C. inthe dark for 30 mM before their fluorescence was measured.

The plates containing dye-loaded cells were then flicked to remove thepre-incubation components and washed once with 100 μL/well assay buffer.A 100 μL/well aliquot of assay buffer was added back to the plate, andthe real-time assay was commenced. The fluorescence of cells wasmeasured using a fluorescence plate reader (FLIPR^(TETRA)® or FLIPR384®,MDS, Molecular Devices, Sunnyvale, Calif.) Samples were excited byeither a laser or a PMT light source (Excitation wavelength=470-495 nM)and the emissions are filtered (Emission wavelength=515-575 nM). Theadditions of compound and the channel activators in this cell-based,medium-to-high throughput assay were performed on the fluorescence platereader and the results (expressed as relative fluorescence units) werecaptured by means of camera shots every 1-3 sec., then displayed inreal-time and stored. Generally, there was a 15 sec. base line, withcamera shots taken every 1.5 sec., then the test compounds were added,then another 120 sec. baseline was conducted, with camera shots takenevery 3 sec.; and finally, the agonist solution (containing veratridineand scorpion venom) was added. The amplitude of fluorescence increase,resulting from the binding of Na⁺ ions to the CoroNa™ Green dye, wascaptured for 180 sec. thereafter. Results were expressed in relativefluorescence units (RFU) and can be determined by using the maximumsignal during the latter part of the stimulation; or the maximum minusthe minimum during the whole agonist stimulation period; or by takingthe area under the curve for the whole stimulation period.

The assay can be performed as a screening assay as well with the testarticles present in standard amounts (e.g., 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen were typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gated sodium channels or otherbiologically relevant target molecules.

FLIPR® or FLIPR^(TETRA)® Membrane Potential Assay with KCl and TestArticle Pre-Incubation:

Cells are prepared by plating the recombinant HEK293 cells or other hostcells expressing either recombinant or non-recombinant, native,Na_(v)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of 40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately less cells andmedia. The plate is then incubated in growth media, with or withoutselective antibiotic, overnight at 37° C. at 5% CO₂, 95% humidity, inpreparation for the assay (see, e.g., Benjamin et. al., J. Biomol.Screen 10(4):365-373 (2005)). For screens and counter-screens of othervoltage-gated sodium channels, the assay protocol is similar, thoughoptimal densities of cells, media and subsequent assay components can befine-tuned for the particular cell line or sodium channel isoform beingtested.

The next day, at the start of the assay, the media is flicked from thecells and the wells are washed once with 50 μL/well assay buffer (1×Hank's balanced salt solution without sodium bicarbonate or phenol red,20 mM Hepes, pH 7.3) and then pre-incubated with the test articles, themembrane potential dye (for cell loading), and the KCl forre-polarization and synchronization of the channels in the entirepopulation of cells. For this dye-loading and pre-stimulation step, thecomponents are added as follows, immediately after the wash step: 1)first, the compound dilutions and controls are added as 4× concentratesin assay buffer at 50 μL/well; 2) membrane potential dye is diluted fromthe stock solution in assay buffer (4× concentrate) and added to theplate at 50 μL/well; and 3) finally, a solution of 180 mM KCl (2×) isprepared by diluting a 2M stock solution into assay buffer and thesolution added to the cells at 100 μL/well. The cells are incubated at37° C. in the dark for 30-60 min before their fluorescence is measured.

The plates containing dye-loaded cells are then flicked to remove thepre-incubation components and washed once with 50 μL/well assay buffer.A 50 μL/well aliquot of membrane potential dye is added back to theplate, and the real-time assay is commenced. The fluorescence of cellsis measured using a fluorescence plate reader (FLIPR^(TETRA)® orFLIPR384®, MDS, Molecular Devices, Sunnyvale, Calif.). Samples areexcited by either a laser or a PMT light source (Excitationwavelength=510-545 nM) and the emissions are filtered (Emissionwavelength=565-625 nM). The additions of the compounds (first) and thenthe channel activators (later) in this are performed on the fluorescenceplate reader and the results, expressed as relative fluorescence units(RFU), are captured by means of camera shots every 1-3 sec., thendisplayed in real-time and stored. Generally, there is a 15 sec. baseline, with camera shots taken every 1.5 sec., then the test compoundsare added, then another 120 sec. baseline is conducted, with camerashots taken every 3 sec.; and finally, the agonist solution (containingveratridine and scorpion venom) is added. The amplitude of fluorescenceincrease, resulting from the detection of membrane potential change, iscaptured for 120 sec. thereafter. Results are expressed in relativefluorescence units (RFU) and can be determined by using the maximumsignal during the latter part of the stimulation; or the maximum minusthe minimum during the whole stimulation period; or by taking the areaunder the curve for the whole stimulation period.

The assay can be performed as a screening assay as well with the testarticles present in standard amounts (e.g., 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen are typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

FLIPR® or FLIPR^(TETRA)® Sodium Dye Assay without KCl and Test ArticlePre-Incubation:

Cells are prepared by plating the recombinant HEK293 cells or other hostcells expressing either recombinant or non-recombinant, native,Na_(v)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of 40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately less cells andmedia. The plate is then incubated in growth media, with or withoutselective antibiotic, overnight at 37° C. at 5% CO₂, 95% humidity, inpreparation for the assay. For counter-screens of other voltage-gatedsodium channels, the procedure is very similar, though optimal densitiesof cells, media and subsequent assay components can be fine-tuned forthe particular cell line or isoform.

The next day, at the start of the assay, the media is flicked from thecells and the wells washed once with 50 μL/well assay buffer (1× Hank'sbalanced salt solution without sodium bicarbonate or phenol red, 20 mMHepes, pH 7.3). Membrane potential dye is then added to each well of the96-well plate (50 μL/well), from a freshly diluted sample of the stock(now at 4× concentration) in the assay buffer. The cells are incubatedat 37° C. in the dark for 30-60 mM before their fluorescence ismeasured.

In this standard membrane potential assay, the 96-well plate containingdye-loaded cells is then loaded directly onto the plate reader withoutaspirating the dye solution and without any further washing of thecells. The fluorescence of cells is measured using a fluorescence platereader (FLIPR^(TETRA)® or FLIPR384®, MDS, Molecular Devices, Sunnyvale,Calif.). Samples are excited by either a laser or a PMT light source(Excitation wavelength=510-545 nM) and the emissions are filtered(Emission wavelength=565-625 nM). The additions of the compounds (first,50 μL/well from a 4× stock plate) and then the channel activators(later, 100 μL/well from a 2× stock solution) in this kinetic assay areperformed on the fluorescence plate reader and the results, expressed asrelative fluorescence units (RFU), are captured by means of camera shotsevery 1-3 sec., then displayed in real-time and stored. Generally, thereis a 15 sec. base line, with camera shots taken every 1.5 sec., then thetest compounds are added, then another 120 sec. baseline is conducted,with camera shots taken every 3 sec.; and finally, the agonist solution(containing veratridine and scorpion venom) is added. The amplitude offluorescence increase, resulting from the detection of membranepotential change, is captured for 120 sec. thereafter. Results areexpressed in relative fluorescence units (RFU) and can be determined byusing the maximum signal during the latter part of the stimulation; orthe maximum minus the minimum during the whole stimulation period; or bytaking the area under the curve for the whole stimulation period.

The assay can be performed as a screening assay as well, with the testarticles present in standard amounts (e.g. 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen are typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

Electrophysiology Assay

Cells Manual Electrophysiology:

The hNa_(v)1.7 expressing HEK-293 cells are plated on 35 mm culturedishes pre-coated with poly-D-lysine in standard DMEM culture media(Mediatech, Inc., Herndon, Va.) and incubated in a 5% CO₂ incubator at37° C. Cultured cells are used approximately 12-48 hours after plating.

Cells Automated Electrophysiology:

The hNa_(v)1.7 expressing HEK-293 cells are plated on tissue cultureflasks in standard DMEM culture media (Mediatech, Inc.) and incubated ina 5% CO₂ incubator at 37° C. Cultured cells are used approximately 12-48hours after plating.

Manual Electrophysiology:

On the day of experimentation, the 35 mm dish is placed on the stage ofan inverted microscope equipped with a perfusion system thatcontinuously perfuses the culture dish with fresh recording media. Agravity driven superfusion system is used to apply test solutionsdirectly to the cell under evaluation. This “shooter” system consists ofan array of glass pipettes connected to a motorized horizontaltranslator. The outlet of the shooter is positioned approximately 100 μmfrom the cell of interest.

Whole cell currents are recorded using the whole-cell patch clampconfiguration using an Axopatch 200B amplifier (Axon Instruments, FosterCity Calif.), 1322A A/D converter (Axon Instruments) and pClamp software(v. 8; Axon Instruments) and stored on a personal computer. Gigasealsare formed and the whole-cell configuration is established in voltageclamp mode, and membrane currents generated by hNa_(v)1.7 channels arerecorded. Borosilicate glass pipettes with resistance values between 1.5and 2.0 MΩ when filled with pipette solution are used and seriesresistance (<5 MΩ) is compensated by 75-80%. Signals are sampled at 50kHz and low pass filtered at 3 kHz.

Automated Electrophysiology: On the day of experimentation, cells areprepared by removing media and digesting with appropriate enzymes tosuspend cells in external solution.

Whole cell currents are recorded using the whole-cell patch clampconfiguration using an Patchliner (Nanion Technologies, Munich Germany),EPC 10 quadro amplifiers (HEKA, Bellmore, N.Y.) and PatchControl HT10905 (Nanion Technologies) and PatchMaster v2x73 software (HEKA) andstored on a personal computer. Gigaseals are formed and the whole-cellconfiguration is established in voltage clamp mode, and membranecurrents generated by hNa_(v)1.7 are recorded. NPC-16 chips haveresistance values between 1.0 and 2.0 MΩ when filled with pipettesolution and series resistance (<5 MΩ). Signals are sampled at 25 kHzand low pass filtered at 3 kHz.

Voltage Protocols Manual Electrophysiology:

After establishing the whole-cell configuration in voltage clamp mode,voltage protocols are run to establish the 1) test potential (V_(max)),2) holding potential (V_(h)), and 3) the conditioning potential for eachcell.

After establishing the whole-cell configuration in voltage clamp mode, astandard I-V protocol is run to determine the potential at which themaximal current (I_(max)) is elicited. This potential is the testpotential (V_(t)). To determine a conditioning potential at which 100%of channels are in the inactivated state, a standard steady-stateinactivation (SSIN) protocol is run using a series of fifteen 100ms-long depolarizing prepulses, incrementing in 10 mV steps, immediatelyfollowed by a 5 ms testing pulse to V_(max). This protocol also permitsdetermination of the holding potential at which all channels are in theresting state.

For compounds causing significant retardation of recovery frominactivation, an estimate of the affinity for the inactivated state ofthe channel (K_(i)) is generated using the following protocol. From thenegative, no residual inactivation, holding potential, the cell isdepolarized to the conditioning voltage for 2-5 seconds, returned to thenegative holding potential for 10-20 ms to relieve fast inactivation andthen depolarized to the test potential for ˜15 ms. This voltage protocolis repeated every 10-15 seconds, first to establish a baseline in theabsence of the test compound, then in the presence of the test compound.

After a stable baseline is established, the test compound is applied andblock of the current elicited by the test pulse assessed. In some cases,multiple cumulative concentrations are applied to identify aconcentration that blocked between 40-60% of this current. Washout ofthe compound is attempted by superfusing with control solution oncesteady-state block is observed. An estimate of the K_(i) is calculatedas follows:K _(i)=[drug]*{FR/(1−FR)},  Eq. 1

where [drug] is the concentration of a drug, andFR=I(after drug)/I(control),  Eq. 2

where I is the peak current amplitude. If multiple concentrations wereused, K_(i) is determined from the fit of a logistic equation to FRsplotted against corresponding drug concentrations.

In the alternative, the voltage clamp protocol to examine hNa_(v)1.7currents is as follows. After establishing the whole-cell configurationin voltage clamp mode, two voltage protocols were run to establish: 1)the holding potential; and 2) the test potential for each cell.

Resting Block:

To determine a membrane potential at which the majority of channels arein the resting state, a standard steady-state inactivation (SSIN)protocol is run using 100 ms prepulses×10 mV depolarizing steps. Theholding potential for testing resting block (V_(h1)) is typically 20 mVmore hyperpolarized than the first potential where inactivation isobserved with the inactivation protocol.

From this holding potential a standard I-V protocol is run to determinethe potential at which the maximal current is elicited (V_(max)). Thispotential is the test potential (V_(t)).

The compound testing protocol is a series of 10 ms depolarizations fromthe Vh1 (determined from the SSIN) to the V_(t) (determined from the I-Vprotocol) repeated every 10-15 seconds. After a stable baseline isestablished, a high concentration of a test compound (highestconcentration solubility permits or that which provides 50% block) isapplied and block of the current assessed. Washout of the compound isattempted by superfusing with control solution once steady-state blockwas observed. The affinity for the resting state of the channels iscalculated as follows:K _(r)=[drug]*{FR/(1−FR)},  Eq. 3

where [drug] is the concentration of a drug, andFR=I(after drug)/I(control),  Eq. 2

where I is the peak current amplitude and was used for estimatingresting block dissociation constant, K_(r).

Block of Inactivated Channels:

To assess the block of inactivated channels the holding potential isdepolarized such that 20-50% of the current amplitude is reduced whenpulsed to the same V_(t) as above. This is the second holding potential(V_(h2)). The magnitude of this depolarization depends upon the initialcurrent amplitude and the rate of current loss due to slow inactivation.The current reduction is recorded to determine the fraction of availablechannels at this potential (h).h=I@V _(h2) /I _(max).  Eq. 4

At this membrane voltage a proportion of channels are in the inactivatedstate, and thus inhibition by a blocker includes interaction with bothresting and inactivated channels.

To determine the potency of the test compound on inactivated channels, aseries of currents are elicited by 10 ms voltage steps from V_(h2) toV_(t) every 10-15 seconds. After establishing a stable baseline, the lowconcentration of the compound is applied. In some cases, multiplecumulative concentrations will have to be applied to identify aconcentration that blocks between 40-60% of the current. Washout isattempted to re-establish baseline. Fractional responses are measuredwith respect to a projected baseline to determine K_(app).K _(app)=[drug]*{FR/(1−FR)},  Eq. 5where [drug] is the concentration of a drug.

This K_(app) value, along with the calculated K_(r) and h values, areused to calculate the affinity of the compound for the inactivatedchannels (K_(i)) using the following equation:Ki=(1−h)/((1/K _(app))−(h/K _(r))).  Eq. 6

Voltage Protocols Automated Electrophysiology:

Similar voltage protocols are used as described above, however the testpotential (V_(t)) is set to a predetermined voltage. K_(app) isdetermined as described above.

Solutions and Chemicals:

For electrophysiological recordings the external solution is eitherstandard, HBSS supplemented with 10 mM HEPES (pH adjusted to 7.34 withNaOH and the osmolarity adjusted to 320) or Tyrodes salt solution(Sigma, USA) supplemented with 10 mM HEPES (pH adjusted to 7.4 withNaOH; osmolarity=320). The internal pipette solution contains (in mM):NaCl (10), CsF (140), CaCl2 (1), MgCl2 (5), EGTA (11), HEPES (10: pH7.4, 305 mOsm). Compounds are prepared first as series of stocksolutions in DMSO and then dissolved in external solution; DMSO contentin final dilutions did not exceed 0.3%. At this concentration, DMSO doesnot affect sodium currents. Vehicle solution used to establish base linealso contains 0.3% DMSO.

Data Analysis Manual Electrophysiology:

Data is analyzed off-line using Clampfit software (pClamp, v.8; AxonInstruments) and graphed using GraphPad Prizm (v. 4.0) software.

Data Analysis Automated Electrophysiology:

Data is analyzed off-line using Igor Pro (v 6.2.2.2; Wave Metrics, Inc.,Lake Oswego, Oreg.) and Microsoft XL (Microsoft Office 2010, v14x,Microsoft, Renton Wash.).

In Vivo Assay for Pain

Compounds of the Disclosure can be tested for their antinociceptiveactivity in the formalin model as described in Hunskaar et al., J.Neurosci. Methods 14: 69-76 (1985). Male Swiss Webster NIH mice (20-30g; Harlan, San Diego, Calif.) can be used in all experiments. Food iswithdrawn on the day of the experiment. Mice are placed in Plexiglassjars for at least 1 hour to acclimate to the environment. Following theacclimation period, mice are weighed and given either the compound ofinterest administered i.p. or p.o., or the appropriate volume of vehicle(for example, 10% Tween-80 or 0.9% saline, and other pharmaceuticallyacceptable vehicles) as control. Fifteen minutes after the i.p. dosing,and 30 minutes after the p.o. dosing mice are injected with formalin (20μL of 5% formaldehyde solution in saline) into the dorsal surface of theright hind paw. Mice are transferred to the Plexiglass jars andmonitored for the amount of time spent licking or biting the injectedpaw. Periods of licking and biting are recorded in 5-minute intervalsfor 1 hour after the formalin injection. All experiments are done in ablinded manner during the light cycle. The early phase of the formalinresponse is measured as licking/biting between 0-5 minutes, and the latephase is measured from 15-50 minutes. Differences between vehicle anddrug treated groups can be analyzed by one-way analysis of variance(ANOVA). A P value <0.05 is considered significant. Compounds areconsidered to be efficacious for treating acute and chronic pain if theyhave activity in blocking both the early and second phase offormalin-induced paw-licking activity.

In Vivo Assays for Inflammatory or Neuropathic Pain

Test Animals:

Each experiment uses rats weighing between 200-260 g at the start of theexperiment. The rats are group-housed and have free access to food andwater at all times, except prior to oral administration of a testcompound when food is removed for 16 h before dosing. A control groupacts as a comparison to rats treated with a Compound of the Disclosure.The control group is administered the carrier as used for the testcompound. The volume of carrier administered to the control group is thesame as the volume of carrier and test compound administered to the testgroup.

Inflammatory Pain:

To assess the actions of Compounds of the Disclosure on the treatment ofinflammatory pain, the Freund's complete adjuvant (“FCA”) model ofinflammatory pain is used. FCA-induced inflammation of the rat hind pawis associated with the development of persistent inflammatory mechanicaland thermal hyperalgesia and provides reliable prediction of theanti-hyperalgesic action of clinically useful analgesic drugs (Bartho etal., Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670 (1990)).Prior to the injury, the animal is assessed for response to noxiousmechanical stimuli by determining the paw withdrawal threshold (PWT), orto noxious thermal stimuli by determining paw withdrawal latency (PWL),as described below (baseline PWT or PWL). Then, the left hind paw ofeach animal is administered a 50 μL intraplantar injection of 50% FCA.24 hour post injection, the PWT or PWL is again assessed(pre-administration PWT or PWL). Rats are then administered a singleinjection of either a test compound or 30 mg/Kg of a positive controlcompound (e.g., indomethacin). Responses to noxious mechanical orthermal stimuli are then determined 1, 3, 5 and 24 hours postadministration (post-administration PWT or PWL). Percentage reversal ofhyperalgesia for each animal is defined as:

${\%\mspace{14mu}{reversal}} = {\frac{\begin{matrix}\lbrack {( {{post}\mspace{14mu}{administration}\mspace{14mu}{PWT}\mspace{14mu}{or}\mspace{14mu}{PWL}} ) -}  \\ ( {{pre}\text{-}{administration}\mspace{14mu}{PWT}\mspace{14mu}{or}\mspace{14mu}{PWL}} ) \rbrack\end{matrix}}{\begin{matrix}\lbrack {( {{baseline}\mspace{14mu}{PWT}\mspace{14mu}{or}\mspace{14mu}{PWL}} ) -}  \\ ( {{pre}\text{-}{administration}\mspace{14mu}{PWT}\mspace{14mu}{or}\mspace{14mu}{PWL}} ) \rbrack\end{matrix}} \times 100}$

Neuropathic Pain:

To assess the actions of the test compounds for the treatment ofneuropathic pain the Seltzer model or the Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats(Seltzer et al., Pain 43:205-218 (1990)). Partial ligation of the leftsciatic nerve is performed under isoflurane/O₂ inhalation anesthesia.Following induction of anesthesia, the left thigh of the rat is shavedand the sciatic nerve exposed at high thigh level through a smallincision and is carefully cleared of surrounding connective tissues at asite near the trocanther just distal to the point at which the posteriorbiceps semitendinosus nerve branches off of the common sciatic nerve. A7-0 silk suture is inserted into the nerve with a ⅜ curved,reversed-cutting mini-needle and tightly ligated so that the dorsal ⅓ to½ of the nerve thickness is held within the ligature. The wound isclosed with a single muscle suture (4-0 nylon (Vicryl)) and vetbondtissue glue. Following surgery, the wound area is dusted with antibioticpowder. Sham-treated rats undergo an identical surgical procedure exceptthat the sciatic nerve is not manipulated. Following surgery, animalsare weighed and placed on a warm pad until they recover from anesthesia.Animals are then returned to their home cages until behavioral testingbegins. The animals are assessed for response to noxious mechanicalstimuli by determining PWT, as described below, prior to surgery(baseline), then immediately prior to and 1, 3, and 5 hours afteradministration of either drug or vehicle, for the ipsilateral (injuredside) rear paw of the animal. Percentage reversal of neuropathichyperalgesia is defined as:

${\%\mspace{14mu}{reversal}} = {\frac{\begin{matrix}\lbrack {( {{post}\mspace{14mu}{administration}\mspace{14mu}{PWT}} ) -}  \\ ( {{pre}\text{-}{administration}\mspace{14mu}{PWT}} ) \rbrack\end{matrix}}{\begin{matrix}\lbrack {( {{baseline}\mspace{14mu}{PWT}} ) -}  \\ ( {{pre}\text{-}{administration}\mspace{14mu}{PWT}} ) \rbrack\end{matrix}} \times 100}$

In the Chung model, the spinal nerve ligation (SNL) model of neuropathicpain is used to produce mechanical hyperalgesia, thermal hyperalgesia,and tactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anesthesia. Following induction of anesthesia a 3 cm incisionis made and the left paraspinal muscles are separated from the spinousprocess at the L₄-S₂ levels. The L₆ transverse process is carefullyremoved with a pair of small rongeurs to identify visually the L₄-L₆spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) is (are)isolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is (are)not manipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after being administered a Compound of theDisclosure or vehicle, for the left rear paw of the animal. The animalscan also be assessed for response to noxious thermal stimuli or fortactile allodynia, as described below. The Chung model for neuropathicpain is described in Kim et al., Pain 50(3):355-363 (1992).

Tactile Allodynia:

Sensitivity to non-noxious mechanical stimuli can be measured in animalsto assess tactile allodynia. Rats are transferred to an elevated testingcage with a wire mesh floor and allowed to acclimate for five to tenminutes. A series of von Frey monofilaments are applied to the plantarsurface of the hindpaw to determine the animal's withdrawal threshold.The first filament used possesses a buckling weight of 9.1 gms (0.96 logvalue) and is applied up to five times to see if it elicits a withdrawalresponse. If the animal has a withdrawal response, then the nextlightest filament in the series would be applied up to five times todetermine if it also could elicit a response. This procedure is repeatedwith subsequent lesser filaments until there is no response and theidentity of the lightest filament that elicits a response is recorded.If the animal does not have a withdrawal response from the initial 9.1gms filament, then subsequent filaments of increased weight are applieduntil a filament elicits a response and the identity of this filament isrecorded. For each animal, three measurements are made at every timepoint to produce an average withdrawal threshold determination. Testscan be performed prior to, and at 1, 2, 4 and 24 hours post drugadministration.

Mechanical Hyperalgesia:

Representative Compounds of the Disclosure can be tested in theSNL-induced mechanical hyperalgesia model in rats. Sensitivity tonoxious mechanical stimuli are measured in animals using the pawpressure test to assess mechanical hyperalgesia. In rats, hind pawwithdrawal thresholds (“PWT”), measured in grams, in response to anoxious mechanical stimulus are determined using an analgesymeter (Model7200, commercially available from Ugo Basile of Italy), as described inStein (Biochemistry & Behavior 31: 451-455 (1988)). The rat's paw isplaced on a small platform, and a punctate weight was applied in agraded manner up to a maximum of 250 grams. The endpoint is taken as theweight at which the paw is completely withdrawn. PWT is determined oncefor each rat at each time point. PWT can be measured only in the injuredpaw, or in both the injured and non-injured paw. Rats are tested priorto surgery to determine a baseline, or normal, PWT. Rats are testedagain 2 to 3 weeks post-surgery, prior to, and at different times after(e.g. 1, 3, 5 and 24 hr) drug administration. An increase in PWTfollowing drug administration indicates that the test compound reducesmechanical hyperalgesia.

In Vivo Assay for Anticonvulsant Activity

Compounds of the Disclosure can be tested for in vivo anticonvulsantactivity after i.v., p.o., or i.p. injection using any of a number ofanticonvulsant tests in mice or rats, including the maximum electroshockseizure test (MES). Maximum electroshock seizures are induced in maleNSA mice weighing between 15-20 g and in male Sprague-Dawley ratsweighing between 200-225 g by application of current (for mice: 50 mA,60 pulses/sec, 0.8 msec pulse width, 1 sec duration, D.C.; for rats: 99mA, 125 pulses/sec, 0.8 msec pulse width, 2 sec duration, D.C.) using aUgo Basile ECT device (Model 7801). Mice are restrained by gripping theloose skin on their dorsal surface and saline-coated corneal electrodesare held lightly against the two corneae. Rats are allowed free movementon the bench top and ear-clip electrodes are used. Current is appliedand animals are observed for a period of up to 30 seconds for theoccurrence of a tonic hindlimb extensor response. A tonic seizure isdefined as a hindlimb extension in excess of 90 degrees from the planeof the body. Results can be treated in a quantal manner.

Pharmaceutical Compositions

Compounds of the Disclosure can be administered to a mammal in the formof a raw chemical without any other components present. Compounds of theDisclosure can also be administered to a mammal as part of apharmaceutical composition containing the compound combined with asuitable pharmaceutically acceptable carrier. Such a carrier can beselected from pharmaceutically acceptable excipients and auxiliaries.

Pharmaceutical compositions within the scope of the present disclosureinclude all compositions where a Compound of the Disclosure is combinedwith one or more pharmaceutically acceptable carriers. In oneembodiment, the Compound of the Disclosure is present in the compositionin an amount that is effective to achieve its intended therapeuticpurpose. While individual needs may vary, a determination of optimalranges of effective amounts of each compound is within the skill of theart. Typically, a Compound of the Disclosure can be administered to amammal, e.g., a human, orally at a dose of from about 0.0025 to about1500 mg per kg body weight of the mammal, or an equivalent amount of apharmaceutically acceptable salt or solvate thereof, per day to treatthe particular disorder. A useful oral dose of a Compound of theDisclosure administered to a mammal is from about 0.0025 to about 50 mgper kg body weight of the mammal, or an equivalent amount of thepharmaceutically acceptable salt or solvate thereof. For intramuscularinjection, the dose is typically about one-half of the oral dose.

A unit oral dose may comprise from about 0.01 mg to about 1 g of theCompound of the Disclosure, e.g., about 0.01 mg to about 500 mg, about0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, 0.01 mg to about50 mg, e.g., about 0.1 mg to about 10 mg, of the compound. The unit dosecan be administered one or more times daily, e.g., as one or moretablets or capsules, each containing from about 0.01 mg to about 1 g ofthe compound, or an equivalent amount of a pharmaceutically acceptablesalt or solvate thereof.

A pharmaceutical composition of the present disclosure can beadministered to any animal that may experience the beneficial effects ofa Compound of the Disclosure. Foremost among such animals are mammals,e.g., humans and companion animals, although the disclosure is notintended to be so limited.

A pharmaceutical composition of the present disclosure can beadministered by any means that achieves its intended purpose. Forexample, administration can be by the oral, parenteral, subcutaneous,intravenous, intramuscular, intraperitoneal, transdermal, intranasal,transmucosal, rectal, intravaginal or buccal route, or by inhalation.The dosage administered and route of administration will vary, dependingupon the circumstances of the particular subject, and taking intoaccount such factors as age, gender, health, and weight of therecipient, condition or disorder to be treated, kind of concurrenttreatment, if any, frequency of treatment, and the nature of the effectdesired.

In one embodiment, a pharmaceutical composition of the presentdisclosure can be administered orally and is formulated into tablets,dragees, capsules or an oral liquid preparation. In one embodiment, theoral formulation comprises extruded multiparticulates comprising theCompound of the Disclosure.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered rectally, and is formulated in suppositories.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered by injection.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered transdermally.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered by inhalation or by intranasal or transmucosaladministration.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered by the intravaginal route.

A pharmaceutical composition of the present disclosure can contain fromabout 0.01 to 99 percent by weight, and preferably from about 0.25 to 75percent by weight, of active compound(s).

A method of the present disclosure, such as a method for treating oralleviating symptoms thereof of a disorder responsive to the blockade ofsodium channels in an animal in need thereof, can further compriseadministering a second therapeutic agent to the animal in combinationwith a Compound of the Disclosure. In one embodiment, the othertherapeutic agent is administered in an effective amount.

Effective amounts of the other therapeutic agents are known to thoseskilled in the art. However, it is well within the skilled artisan'spurview to determine the other therapeutic agent's optimaleffective-amount range.

Compounds of the Disclosure (i.e., the first therapeutic agent) and thesecond therapeutic agent can act additively or, in one embodiment,synergistically. Alternatively, the second therapeutic agent can be usedto treat a disorder or condition that is different from the disorder orcondition for which the first therapeutic agent is being administered,and which disorder or condition may or may not be a condition ordisorder as defined herein. In one embodiment, a Compound of theDisclosure is administered concurrently with a second therapeutic agent;for example, a single composition comprising both an effective amount ofa Compound of the Disclosure and an effective amount of the secondtherapeutic agent can be administered. Accordingly, the presentdisclosure further provides a pharmaceutical composition comprising acombination of a Compound of the Disclosure, the second therapeuticagent, and a pharmaceutically acceptable carrier. Alternatively, a firstpharmaceutical composition comprising an effective amount of a Compoundof the Disclosure and a second pharmaceutical composition comprising aneffective amount of the second therapeutic agent can be concurrentlyadministered. In another embodiment, an effective amount of a Compoundof the Disclosure is administered prior or subsequent to administrationof an effective amount of the second therapeutic agent. In thisembodiment, the Compound of the Disclosure is administered while thesecond therapeutic agent exerts its therapeutic effect, or the secondtherapeutic agent is administered while the Compound of the Disclosureexerts its therapeutic effect for treating a disorder or condition.

The second therapeutic agent can be an opioid agonist, a non-opioidanalgesic, a non-steroidal anti-inflammatory agent, an antimigraineagent, a Cox-II inhibitor, a β-adrenergic blocker, an anticonvulsant, anantidepressant, an anticancer agent, an agent for treating addictivedisorder, an agent for treating Parkinson's disease and parkinsonism, anagent for treating anxiety, an agent for treating epilepsy, an agent fortreating a seizure, an agent for treating a stroke, an agent fortreating a pruritic condition, an agent for treating psychosis, an agentfor treating ALS, an agent for treating a cognitive disorder, an agentfor treating a migraine, an agent for treating vomiting, an agent fortreating dyskinesia, or an agent for treating depression, or a mixturethereof.

A pharmaceutical composition of the present disclosure is manufacturedin a manner which itself will be known in view of the instantdisclosure, for example, by means of conventional mixing, granulating,dragee-making, dissolving, extrusion, or lyophilizing processes. Thus,pharmaceutical compositions for oral use can be obtained by combiningthe active compound with solid excipients, optionally grinding theresulting mixture and processing the mixture of granules, after addingsuitable auxiliaries, if desired or necessary, to obtain tablets ordragee cores.

Suitable excipients include fillers such as saccharides (for example,lactose, sucrose, mannitol or sorbitol), cellulose preparations, calciumphosphates (for example, tricalcium phosphate or calcium hydrogenphosphate), as well as binders such as starch paste (using, for example,maize starch, wheat starch, rice starch, or potato starch), gelatin,tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one ormore disintegrating agents can be added, such as the above-mentionedstarches and also carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodiumalginate.

Auxiliaries are typically flow-regulating agents and lubricants such as,for example, silica, talc, stearic acid or salts thereof (e.g.,magnesium stearate or calcium stearate), and polyethylene glycol. Drageecores are provided with suitable coatings that are resistant to gastricjuices. For this purpose, concentrated saccharide solutions can be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations such as acetylcellulose phthalate orhydroxypropylmethyl-cellulose phthalate can be used. Dye stuffs orpigments can be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Examples of other pharmaceutical preparations that can be used orallyinclude push-fit capsules made of gelatin, or soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain a compound in the form of granules, which can bemixed with fillers such as lactose, binders such as starches, and/orlubricants such as talc or magnesium stearate and, optionally,stabilizers, or in the form of extruded multiparticulates. In softcapsules, the active compounds are preferably dissolved or suspended insuitable liquids, such as fatty oils or liquid paraffin. In addition,stabilizers can be added.

Possible pharmaceutical preparations for rectal administration include,for example, suppositories, which consist of a combination of one ormore active compounds with a suppository base. Suitable suppositorybases include natural and synthetic triglycerides, and paraffinhydrocarbons, among others. It is also possible to use gelatin rectalcapsules consisting of a combination of active compound with a basematerial such as, for example, a liquid triglyceride, polyethyleneglycol, or paraffin hydrocarbon.

Suitable formulations for parenteral administration include aqueoussolutions of the active compound in a water-soluble form such as, forexample, a water-soluble salt, alkaline solution, or acidic solution.Alternatively, a suspension of the active compound can be prepared as anoily suspension. Suitable lipophilic solvents or vehicles for such assuspension may include fatty oils (for example, sesame oil), syntheticfatty acid esters (for example, ethyl oleate), triglycerides, or apolyethylene glycol such as polyethylene glycol-400 (PEG-400). Anaqueous suspension may contain one or more substances to increase theviscosity of the suspension, including, for example, sodiumcarboxymethyl cellulose, sorbitol, and/or dextran. The suspension mayoptionally contain stabilizers.

The following examples are illustrative, but not limiting, of thecompounds, compositions, and methods of the present disclosure. Suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art in view of this disclosure arewithin the spirit and scope of the disclosure.

EXAMPLES Example 1 Synthesis of(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxamide(Compound 5)

A mixture of Compound 1 (34.828 g, 0.200 mol) (Aldrich), phosphorusoxychloride (100 mL, 1.092 mol) and 20 drops of DMF were heated at 110°C. overnight. After cooling the dark mixture was diluted with hexanes(500 mL) and vigorously stirred. The hexane layer was decanted, quicklywashed with water (100 mL), brine (100 mL) and dried over MgSO₄. Theorganic layer was filtered and carefully evaporated in vacuo to give26.13 g (62%) of Compound 2 as a light yellow liquid. ¹H NMR (400 MHz,CDCl₃): δ 7.93 (s, 1H).

To a solution of Compound 2 (26.13 g, 123.6 mmol) in Et₂O (500 mL) wasadded a mixture of 0.5 M NH₃ in dioxane (250 mL, 125 mmol) and DIPEA (22mL, 126 mmol) dropwise over 50 min. After stirring at RT overnight thereaction mixture was concentrated in vacuo to give a residue that waspurified by flash chromatography (SiO₂, 10-50% EtOAc/hexanes). Theproduct obtained was triturated with 10 mL 10% EtOAc/hexanes andfiltered to give 9.74 g (41%) of Compound 3 as an orange crystallinesolid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.40 (br s, 1H), 8.16 (br s, 1H),8.10 (s, 1H). LC/MS: m/z=192 [M+H]⁺ (Calc: 191).

To a solution of Compound 3 (4.80 g, 25.0 mmol) in ACN (100 mL) wasadded (S)-2-aminopropane carboxamide hydrochloride (Compound 4) (3.18 g,25.54 mmol) and DIPEA (9.60 mL, 55.11 mmol). The mixture was heated at50° C. overnight then concentrated in vacuo. The residue was purified byflash chromatography (SiO₂, 20-60% acetone/hexanes) to give 4.81 g (79%)of Compound 5 as a pale tan powder. LC/MS: m/z=244 [M+H]⁺ (Calc: 243).

In a similar manner, the following compounds were prepared:

(S)-2-chloro-6-((2-oxopyrrolidin-3-yl)amino)pyrimidine-4-carboxamide(Compound 6): LC/MS: m/z=256 [M+H]⁺ (Calc: 255); and

(S)-2-chloro-6-((2-oxopyrrolidin-3-yl)oxy)pyrimidine-4-carboxamide(Compound 7): LC/MS: m/z=257 [M+H]⁺ (Calc: 256).

Example 2 Synthesis of(S)-2-chloro-6-(((2-oxopyrrolidin-3-yl)amino)methyl)pyrimidine-4-carboxamide(Compound 12)

A mixture of Compound 8 (1.536 g, 8.23 mmol) (Sigma-Aldrich), NBS (1.757g, 9.87 mmol) and benzoyl peroxide (199 mg, 0.823 mmol) in CCl₄ (43 mL)was purged with argon for 2 min. The mixture was heated at 80° C. underargon for 24 h. Additional NBS (1.757 g, 9.87 mmol) and benzoyl peroxide(199 mg, 0.823 mmol) were added and the mixture heated at 80° C. for anadditional 24 h. After cooling to RT, the mixture was filtered and thefiltrate concentrated. The residue was adsorbed onto SiO₂ and purifiedby flash chromatography (SiO₂, 0-40% EtOAc/hexanes) to give 0.44 g (20%)of Compound 9 as a brown liquid. LC/MS: m/z=266 [M+H]⁺ (Calc: 265).

To a solution of Compound 9 (0.125 g, 1.249 mmol) in ACN (6 mL) andDIPEA (0.121 g, 1.249 mmol) was added a solution of Compound 10 (0.331g, 1.249 mmol) in ACN (2 mL) at RT dropwise. The resulting solution wasstirred at RT for 2 h and concentrated to dryness to give crude Compound11 which was used directly in the next step. LC/MS: m/z=285 [M+H]⁺(Calc: 284).

To a 20 mL vial containing the crude Compound 11 from the previous stepwas added 7N NH₃ in MeOH (12 mL) at RT. The resulting solution wasstirred at RT for 1 h and concentrated to dryness to give crude Compound12 which was used in subsequent steps without purification. LC/MS:m/z=270 [M+H]⁺ (Calc: 269).

Example 3 Synthesis of (S)-1-(6-bromopyridin-2-yl)ethane-1,2-diol(Compound 14)

To a solution of Compound 13 (WO 2012/035421) (2.35 g, 12.77 mmol) int-BuOH (35 mL) and water (35 mL) at 0° C. was added AD-mix-alpha (17.4g, 1.36 g/mmol of vinyl substrate, Sigma-Aldrich). The reaction mixturewas stirred at RT overnight, diluted with water and extracted withEtOAc. The combined organic extracts were washed with brine, dried overMgSO₄, concentrated and the residue purified by flash chromatography(SiO₂, 40-80% EtOAc/hexanes) to give 2.30 g (82%) of Compound 14 as awhite solid. ¹H NMR (400 MHz, CDCl₃): δ 7.61 (t, J=7.6 Hz, 1H), 7.45 (d,J=7.6 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 4.83 (dd, J=10.0, 5.6 Hz, 1H),3.99-3.94 (m, 1H), 3.81 (pent, J=5.6 Hz, 1H), 3.74 (d, J=5.6 Hz, 1H),2.37 (t, J=6.4 Hz, 1H).

Example 4 Synthesis of 7-bromo-4-(4-(trifluoromethyl)phenyl)-2H-chromene(Compound 21) and4,4,5,5-tetramethyl-2-(4-(4-(trifluoromethyl)phenyl)-2H-chromen-7-yl)-1,3,2-dioxaborolane(Compound 23)

To a solution of 3-bromophenol (Compound 15) (2.00 g, 11.56 mmol) in DMF(25 mL) at 0° C. was added NaH (0.509 g, 12.72 mmol, 60%) in smallportions. Vigorous gas evolution was observed. Stirred at 0° C. for 5min and at RT for 20 min. Cooled to 0° C. and slowly added propargylbromide (Compound 16) (80% wt in xylenes) (1.41 mL, 12.72 mmol). Thereaction mixture was warmed to RT and stirred for 30 min. The reactionmixture was carefully quenched by the addition of water and extractedwith EtOAc. The combined organic extracts were washed with water andbrine, dried over MgSO₄, and concentrated. The residue purified by flashchromatography (SiO₂, 0-10% EtOAc/hexanes) to give 2.34 g (96%) ofCompound 17 as a yellow oil. LC/MS: m/z=212 [M+H]⁺ (Calc: 211).

To a solution of Compound 17 (1.250 g, 5.92 mmol) and1-iodo-4-(trifluoromethyl)benzene (Compound 18) (1.611 g, 5.92 mmol) inTHF (20 mL) was added TEA (1.65 mL, 11.85 mmol) followed by Pd(Ph₃P)₂Cl₂(0.125 g, 0.178 mmol) and copper(I) iodide (0.068 g, 0.355 mmol). Aslight exotherm occurred. The mixture was stirred at RT for 1.5 h. Themixture was quenched with water and extracted with EtOAc. The combinedorganic extracts were dried over MgSO₄, concentrated and the residuepurified by flash chromatography (SiO₂, 0-5% EtOAc/hexanes) to give 1.55g (74%) of Compound 19 as a pale yellow oil. LC/MS: m/z=356 [M+H]⁺(Calc: 355).

To a solution of Compound 19 (1.550 g, 4.36 mmol) in DCM (30 mL) in apressure tube was added(acetonitrile)[(2-biphenyl)di-tert-butylphosphine]gold(I)hexafluoro-antimonate (Compound 20) (0.034 g, 0.044 mmol,Sigma-Aldrich). The tube was sealed and heated at 60° C. for 3 h. Aftercooling to RT, the mixture was adsorbed onto SiO₂ and purified by flashchromatography (SiO₂, 0-10% EtOAc/hexanes) to give 1.26 g (81%) ofCompound 21 as a pale yellow oil. LC/MS: m/z=356 [M+H]⁺ (Calc: 355).

To a solution of Compound 21 (0.750 g, 2.11 mmol), Compound 22 (0.563 g,2.22 mmol), and KOAc (0.622 g, 6.34 mmol) in 1,4-dioxane (10 mL) wasadded Pd(dppf)Cl₂ (0.086 g, 0.106 mmol). The reaction was heated at 90°C. overnight. The mixture was cooled to RT and quenched with water. Themixture was extracted with EtOAc. The combined organics were dried overMgSO₄, concentrated and the residue purified by flash chromatography(SiO₂, 0-10% EtOAc/hexanes) to give 0.53 g (63%) of Compound 23 as alight yellow solid. LC/MS: m/z=403 [M+H]⁺ (Calc: 402).

Example 5 Synthesis of(3R,4S)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(4-(trifluoromethyl)phenyl)chroman-3-ol(Compound 25)

To a solution of Compound 21 (0.470 g, 1.32 mmol) in THF (7 mL) at 0° C.was added 1 M borane tetrahydrofuran complex in THF (1.456 mL, 1.456mmol) dropwise. The reaction mixture was stirred at RT overnight. 2.5Maq. NaOH (1.59 mL, 3.97 mmol) was added dropwise. After 5 min themixture was cooled to 0° C. and 30% hydrogen peroxide (1.35 mL, 13.23mmol) was added slowly. After the addition was complete, the mixture washeated at reflux for 2 h. After cooling to RT, water was added and themixture extracted with EtOAc. The combined organic extracts were driedover MgSO₄, concentrated and the residue purified by flashchromatography (SiO₂, 10-30% EtOAc/hexanes) to give 0.208 g (42%) ofCompound 24 as a pale yellow oil. LC/MS: m/z=374 [M+H]⁺ (Calc: 373).

To a mixture of Compound 24 (0.200 g, 0.536 mmol), Compound 22 (0.143 g,0.563 mmol) and KOAc (0.158 g, 1.608 mmol) in 1,4-dioxane (5 mL) wasadded Pd(dppf)Cl₂ (0.022 g, 0.027 mmol). The reaction mixture was heatedat 90° C. overnight, cooled to RT and quenched with water. The mixturewas extracted with EtOAc and the combined organic extracts were driedover MgSO₄, concentrated and the residue purified by flashchromatography (SiO₂, 0-10% EtOAc/hexanes) to give 0.157 g (70%) ofCompound 25 as a light yellow solid. LC/MS: m/z=421 [M+H]⁺ (Calc: 420).

Example 6 Synthesis of tert-butyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxylate(Compound 30)

To a solution of Compound 26 (1.00 g, 6.75 mmol, Matrix Scientific) inMeOH (10 mL) at 0° C. was added Boc₂O (1.55 g, 7.08 mmol). Mild gasevolution was observed. After 15 min the reaction was warmed to RT andstirred for 1 h. The reaction mixture was concentrated and the residuepurified by flash chromatography (SiO₂, 0-40% EtOAc/hexanes) to give1.70 g (99%) of Compound 27 as a white solid. LC/MS: m/z=271 [M+Na]⁺(Calc: 248).

To a solution of Compound 27 (0.95 g, 3.83 mmol) and Compound 18 (1.25g, 4.59 mmol) in toluene (10 mL) were added Cs₂CO₃ (1.75 g, 5.36 mmol),Pd(OAc)₂ (0.043 g, 0.19 mmol), and BINAP (0.119 g, 0.19 mmol). Thereaction mixture was heated at 100° C. overnight, cooled to RT, quenchedwith water and extracted with EtOAc. The combined organic extracts weredried over MgSO₄, concentrated and the residue purified by flashchromatography (SiO₂, 0-15% EtOAc/hexanes) to give 1.33 g (89%) ofCompound 28 as an off-white solid. LC/MS: m/z=415 [M+Na]⁺ (Calc: 392).

To a solution of Compound 28 (0.550 g, 1.40 mmol) in ACN (12 mL) and DCM(2 mL) at 0° C. was added NBS (0.262 g, 1.47 mmol). The reaction mixturewas stirred at 0° C. for 45 min and then concentrated. The residue wastriturated with CCl₄ and the solids were removed via filtration, rinsingwith CCl₄. The filtrate was concentrated and the residue purified byflash chromatography (SiO₂, 10-20% EtOAc/hexanes) to give 0.64 g (97%)of Compound 29 as an off-white solid. LC/MS: m/z=494 [M+H]⁺ (Calc: 493).

To a solution of Compound 29 (1.54 g, 3.27 mmol) and Compound 22 (0.87g, 3.43 mmol) in 1,4-dioxane (20 mL) was added KOAc (0.96 g, 9.80 mmol)and Pd(dppf)Cl₂ (0.133 g, 0.16 mmol). The reaction mixture was heated at90° C. under nitrogen overnight, cooled to RT, diluted with EtOAc andwashed with water. The aqueous layer was extracted with EtOAc and thecombined organic extracts were dried over MgSO₄ and concentrated. Theresidue was purified by flash chromatography (SiO₂, 0-15% EtOAc/hexanes)to give 1.10 g (65%) of Compound 30 as a white solid. LC/MS: m/z=541[M+Na]⁺ (Calc: 518).

In a similar manner the following compounds were prepared:

7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine(Compound 31): LC/MS: m/z=418 [M+H]⁺ (Calc: 417);

7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydrobenzo[e][1,4]oxazepine(Compound 32): LC/MS: m/z=420 [M+H]⁺ (Calc: 419);

8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine(Compound 33): LC/MS: m/z=420 [M+H]⁺ (Calc: 419);

6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline(Compound 34): LC/MS: m/z=404 [M+H]⁺ (Calc: 403);

6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline(Compound 35): LC/MS: m/z=404 [M+H]⁺ (Calc: 403); and

5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)phenyl)indoline (Compound 36): LC/MS: m/z=390 [M+H]⁺ (Calc: 389).

Example 7 Synthesis of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((4-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline(Compound 41)

To a solution of 1,2,3,4-tetrahydroquinoline (Compound 37) (0.200 g,1.502 mmol) in DCM (10 mL) at 0° C. was added TEA (0.314 mL, 2.252 mmol)followed by 4-(trifluoromethyl)benzene-1-sulfonyl chloride (Compound 38)(0.404 g, 1.652 mmol). The reaction mixture was stirred at RT for 2 hand then quenched with water and extracted with DCM. The combinedorganic extracts were washed with 1.0 M aq. HCl, dried over MgSO₄ andconcentrated to give 0.477 g (93%) of Compound 39 as a beige solid whichwas used in subsequent steps without further purification. LC/MS:m/z=342 [M+H]⁺ (Calc: 341).

To a solution of Compound 39 (0.477 g, 1.397 mmol) in ACN (8 mL) at 0°C. was added NBS (0.261 g, 1.467 mmol). The reaction mixture was stirredat 0° C. for 20 min and at RT for 1 h. The mixture was concentrated andthe residue purified by flash chromatography (SiO₂, 0-20% EtOAc/hexanes)to give 0.503 g (86%) of Compound 40 as a white solid. LC/MS: m/z=421[M+H]⁺ (Calc: 420).

To a solution of Compound 40 (0.503 g, 1.20 mmol), Compound 22 (0.334 g,1.317 mmol), and KOAc (0.352 g, 3.59 mmol) in 1,4-dioxane (7 mL) wasadded Pd(dppf)Cl₂ (0.049 g, 0.060 mmol). The reaction mixture was heatedat 90° C. overnight. After cooling to RT, the mixture was extracted withEtOAc. The combined organics were washed with water and brine, driedover MgSO₄, concentrated and the residue purified by flashchromatography (SiO₂, 0-30% EtOAc/hexanes) to give 0.460 g (82%) ofCompound 41 as a white solid. LC/MS: m/z=468 [M+H]⁺ (Calc: 467).

6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinoline(Compound 42) was prepared in a similar manner. LC/MS: m/z=418 [M+H]⁺(Calc: 417).

Example 8 Synthesis of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)benzyl)indolin-2-one (Compound 49)

To a solution of 5-bromo-1H-indole (Compound 43) (2.500 g, 12.75 mmol)in DMF (30 mL) at 0° C. was added NaH (0.612 g, 15.30 mmol, 60%). Themixture was warmed to RT, stirred for 20 min and cooled to 0° C.1-(Bromomethyl)-4-(trifluoromethyl)benzene (Compound 44) (3.35 g, 14.03mmol) was added as a solid. The mixture was warmed to RT and stirred for1 h. The mixture was quenched with water and extracted with EtOAc. Thecombined organic extracts were washed with water and brine, dried overMgSO₄, concentrated and the residue purified by flash chromatography(SiO₂, 0-10% EtOAc/hexanes) to give 4.49 g (99%) of Compound 45 as anoff-white solid. LC/MS: m/z=355 [M+H]⁺ (Calc: 354).

To a solution of Compound 45 (1.000 g, 2.82 mmol) in t-BuOH (20 mL) andwater (1 mL) was added NBS (1.508 g, 8.47 mmol) in portions over 5 min.The mixture was stirred at RT for 1.5 h then concentrated in vacuo. Theresidue was partioned between water and DCM, the layers separated andthe aqueous layer extracted with DCM. The combined organic layers werewashed with 1M aq. NaOH, dried over MgSO₄ and concentrated to give thecrude product as a sticky maroon foam (1.47 g). TLC and LC/MS shows amixture of three products, Compounds 46, 47, and 48. This material wasused in the next step without purification.

To a solution of the mixture of Compounds 46, 47, and 48 (from theprevious step) in AcOH (20 mL) was added zinc powder (1.845 g, 28.2mmol). The reaction became slightly exothermic and a white precipitateformed. The mixture was stirred vigorously at RT for 1 h, filteredthrough a fritted funnel to give a white filter cake and a filtrate. Thefiltrate was concentrated and the residue dissolved in DCM and washedwith sat'd. aq. NaHCO₃. The aqueous phase was back-extracted with DCM.The combined organic extracts were dried over MgSO₄ and concentrated togive a white solid (batch A). The white filter cake from above wassuspended in 1M aq. HCl and extracted with DCM. The combined organicextracts were dried over MgSO₄ and concentrated to give additional whitesolid (batch B). Batches A and B were combined to give 0.765 g (73%) ofCompound 46 as a white solid. LC/MS: m/z=371 [M+H]⁺ (Calc: 370).

To a solution of Compound 46 (0.400 g, 1.08 mmol), Compound 22 (0.288 g,1.14 mmol), and KOAc (0.318 g, 3.24 mmol) in 1,4-dioxane (8 mL) wasadded Pd(dppf)Cl₂ (0.044 g, 0.054 mmol). The reaction was heated at 90°C. overnight. The mixture was cooled to RT and quenched with water. Themixture was extracted with EtOAc. The combined organics were dried overMgSO₄, concentrated and the residue purified by flash chromatography(SiO₂, 0-20% EtOAc/hexanes) to give 0.275 g (61%) of Compound 49 as anorange solid. LC/MS: m/z=418 [M+H]⁺ (Calc: 417).

Example 9 Synthesis of1-cyclohexyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine(Compound 54)

To a mixture of 2,3,4,5-tetrahydro-1H-benzo[b]azepine (Compound 50)(0.295 g, 2.004 mmol), cyclohexanone (Compound 51) (0.415 mL, 4.01 mmol)and AcOH (0.344 mL, 6.01 mmol) in DCE (10 mL) at RT was added NaBH(OAc)₃(1.062 g, 5.01 mmol). The reaction mixture was stirred at RT overnightand quenched by the addition of satd. aq. NaHCO₃. The mixture wasdiluted with water and extracted with DCM. The combined organic extractswere washed with satd. aq. NaHCO₃, dried over MgSO₄ and concentrated togive Compound 52 as yellow oil. This material was used in the next stepwithout purification. LC/MS: m/z=230 [M+H]⁺ (Calc: 229).

To a solution of Compound 52 (0.460 g, 2.006 mmol) in ACN (8 mL) at 0°C. was added NBS (0.375 g, 2.106 mmol). The reaction mixture was stirredat 0° C. for 30 min, concentrated and the residue purified by flashchromatography (SiO₂, 0-5% EtOAc/hexanes) to give 0.480 g (78%) ofCompound 53 as a viscous colorless oil. LC/MS: m/z=309 [M+H]⁺ (Calc:308).

To a solution of Compound 53 (0.480 g, 1.557 mmol), Compound 22 (0.415g, 1.635 mmol), and KOAc (0.458 g, 4.67 mmol) in 1,4-dioxane (8 mL) wasadded Pd(dppf)Cl₂ (0.064 g, 0.078 mmol). The reaction was heated at 90°C. overnight. The mixture was cooled to RT and quenched with water. Themixture was extracted with EtOAc. The combined organics were dried overMgSO₄, concentrated and the residue purified by flash chromatography(SiO₂, 0-5% EtOAc/hexanes) to give 0.353 g (64%) of Compound 54 as anoff-white solid. LC/MS: m/z=356 [M+H]⁺ (Calc: 355).

In a similar manner the following compounds were prepared:

1-(tetrahydro-2H-pyran-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine(Compound 55): LC/MS: m/z=358 [M+H]⁺ (Calc: 357); and

1-(4,4-difluorocyclohexyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine(Compound 56): LC/MS: m/z=392 [M+H]⁺ (Calc: 391).

Example 10 Synthesis of6-(1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)picolinamide(Compound 58)

To a solution of Compound 31 (0.183 g, 0.44 mmol) and Compound 57 (0.080g, 0.40 mmol, Sigma-Aldrich) in DME (2.5 mL) and EtOH (1.5 mL) was addedPd(PPh₃)₂Cl₂ (0.014 g, 0.02 mmol) followed by 2M aq. Na₂CO₃ (0.60 mL,1.20 mmol). The reaction mixture was purged with nitrogen and stirred at85° C. for 1 h. After cooling to RT the reaction was diluted with waterand extracted with EtOAc. The combined organic extracts were dried overMgSO₄, concentrated and the residue purified by flash chromatography(SiO₂, 30-60% EtOAc/hexanes) to give 0.127 g (78%) of Compound 58 as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.39 (d, J=2.0 Hz, 1H), 8.38(br s, 1H), 8.21 (d, J=8.4 Hz, 1H), 8.20 (d, J=8.0 Hz, 1H), 8.07 (t,J=8.0 Hz, 1H), 7.99 (d, J=7.2 Hz, 1H), 7.73 (br s, 1H), 7.45 (d, J=8.6Hz, 2H), 7.30 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.6 Hz, 2H), 3.74 (br s,2H), 2.78-2.68 (m, 2H), 1.86-1.77 (m, 2H), 1.71 (br s, 2H). LC/MS:m/z=412 [M+H]⁺ (Calc: 411).

In a similar manner the following compounds were prepared:

tert-Butyl7-(6-carbamoylpyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxylate(Compound 59): LC/MS: m/z=535 [M+Na]⁺ (Calc: 512);

tert-Butyl(S)-7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxylate(Compound 60): LC/MS: m/z=520 [M+H]⁺ (Calc: 529);

6-(1-(4-(Trifluoromethyl)phenyl)-1,2,3,5-tetrahydrobenzo[e][1,4]oxazepin-7-yl) picolinamide (Compound 61): ¹H NMR (400 MHz,DMSO-d₆): δ 8.52 (s, 1H), 8.41 (br s, 1H), 8.29 (d, J=8.4 Hz, 1H), 8.21(d, J=8.0 Hz, 1H), 8.07 (t, J=7.6 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.75(br s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 1H), 6.92 (d,J=8.4 Hz, 2H), 4.63 (s, 2H), 3.91 (br s, 2H), 3.85 (br s, 2H). LC/MS:m/z=414 [M+H]⁺ (Calc: 413);

(S)-1-(6-(1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydrobenzo[e][1,4]oxazepin-7-yl)pyridin-2-yl)ethane-1,2-diol (Compound 62): ¹H NMR(400 MHz, MeOH-d₄): δ 8.14 (d, J=2.0 Hz, 1H), 8.06 (dd, J=8.0, 2.0 Hz,1H), 7.89 (t, J=8.0 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.53 (d, J=7.6 Hz,1H), 7.46 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.0 Hz, 1H), 6.92 (d, J=8.8 Hz,2H), 4.86 (dd, J=6.8, 4.4 Hz, 1H), 4.66 (s, 2H), 3.97 (dd, J=11.2, 4.4Hz, 1H), 3.94 (s, 4H), 3.80 (dd, J=11.2, 6.8 Hz, 1H). LC/MS: m/z=431[M+H]⁺ (Calc: 430);

(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(5-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)pyrimidine-4-carboxamide(Compound 63): ¹H NMR (400 MHz, DMSO-d₆): δ 8.31 (br s, 1H), 8.24-8.20(m, 2H), 7.95 (d, J=6.8 Hz, 1H), 7.71 (br s, 1H), 7.55 (br s, 1H), 7.51(d, J=8.8 Hz, 2H), 7.25 (d, J=8.8 Hz, 1H), 7.13 (s, 1H), 7.02-6.98 (m,3H), 4.60 (t, J=6.8 Hz, 1H), 4.08 (t, J=5.2 Hz, 2H), 3.96 (t, J=5.2 Hz,2H), 2.04 (t, J=5.2 Hz, 2H), 1.38 (d, J=6.8 Hz, 3H). LC/MS: m/z=501[M+H]⁺ (Calc: 500).

(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)pyrimidine-4-carboxamide(Compound 64): ¹H NMR (400 MHz, DMSO-d₆): δ 8.58 (d, J=1.6 Hz, 1H), 8.43(dd, J=8.0, 1.6 Hz, 1H), 8.32 (br s, 1H), 7.96 (d, J=6.0 Hz, 1H), 7.75(br s, 1H), 7.57 (br s, 1H), 7.44 (d, J=8.8 Hz, 2H), 7.24 (d, J=8.0 Hz,1H), 7.12 (s, 1H), 7.01 (br s, 1H), 6.72 (d, J=8.8 Hz, 2H), 4.59 (t,J=6.8 Hz, 1H), 3.73 (br s, 2H), 2.70 (br s, 2H), 2.83-2.79 (m, 2H), 1.70(br s, 2H), 1.38 (d, J=6.8 Hz, 3H). LC/MS: m/z=499 [M+H]⁺ (Calc: 498);

6-(5-(4-(Trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)picolinamide (Compound 65): ¹H NMR (400 MHz,DMSO-d₆): δ 8.35 (br s, 1H), 8.17 (dd, J=7.6, 0.8 Hz, 1H), 8.07-8.00 (m,3H), 7.99 (t, J=7.6 Hz, 1H), 7.69 (br s, 1H), 7.52 (d, J=8.8 Hz, 2H),7.31 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 4.10 (t, J=5.6 Hz, 2H),3.96 (t, J=5.6 Hz, 2H), 2.05 (pent, J=5.6 Hz, 2H). LC/MS: m/z=414 [M+H]⁺(Calc: 413);

6-(1-(4-(Trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-6-yl)picolinamide(Compound 66): ¹H NMR (400 MHz, DMSO-d₆): δ 8.28 (br s, 1H), 8.13 (d,J=2.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.97 (t, J=8.0 Hz, 1H), 7.93 (dd,J=8.4, 2.0 Hz, 1H), 7.88 (d, J=7.2 Hz, 1H), 7.68 (br s, 1H), 7.67 (d,J=8.6 Hz, 2H), 7.44 (d, J=8.6 Hz, 2H), 7.03 (d, J=8.4 Hz, 1H), 3.72 (t,J=6.0 Hz, 2H), 2.89 (t, J=6.4 Hz, 2H), 2.01 (pent, J=6.0 Hz, 2H). LC/MS:m/z=398 [M+H]⁺ (Calc: 397);

6-(1-(3-(Trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-6-yl)picolinamide(Compound 67): ¹H NMR (400 MHz, DMSO-d₆): δ 8.28 (br s, 1H), 8.09 (d,J=2.0 Hz, 1H), 8.02 (dd, J=8.0, 0.8 Hz, 1H), 7.95 (t, J=8.0 Hz, 1H),7.91 (dd, J=8.4, 2.0 Hz, 1H), 7.86 (dd, J=7.2, 0.8 Hz, 1H), 7.67 (br s,1H), 7.62-7.59 (m, 3H), 7.45-7.43 (m, 1H), 6.80 (d, J=8.8 Hz, 1H), 3.70(t, J=5.6 Hz, 2H), 2.91 (t, J=6.4 Hz, 2H), 2.02 (pent, J=6.0 Hz, 2H).LC/MS: m/z=398 [M+H]⁺ (Calc: 397);

6-(1-(4-(Trifluoromethyl)phenyl)indolin-5-yl)picolinamide (Compound 68):¹H NMR (400 MHz, DMSO-d₆): δ 8.30 (br s, 1H), 8.27 (d, J=0.8 Hz, 1H),8.07 (dd, J=8.0, 0.8 Hz, 1H), 8.06 (dd, J=8.4, 1.6 Hz, 1H), 7.98 (t,J=8.0 Hz, 1H), 7.88 (dd, J=7.6, 0.8 Hz, 1H), 7.70 (br s, 1H), 7.70 (d,J=8.6 Hz, 2H), 7.44 (d, J=8.6 Hz, 2H), 7.34 (d, J=8.4 Hz, 1H), 4.10 (t,J=8.4 Hz, 2H), 3.24 (t, J=8.4 Hz, 2H). LC/MS: m/z=384 [M+H]⁺ (Calc:383);

6-(4-(4-(Trifluoromethyl)phenyl)-2H-chromen-7-yl)picolinamide (Compound69): ¹H NMR (400 MHz, DMSO-d₆): δ 8.33 (br. s., 1H), 8.16 (dd, J=7.8,1.0 Hz, 1H), 8.01-8.08 (m, 1H), 7.96-8.00 (m, 1H), 7.92 (d, J=1.8 Hz,1H), 7.79-7.87 (m, 3H), 7.69 (br. s., 1H), 7.62 (d, J=8.0 Hz, 2H), 7.01(d, J=8.1 Hz, 1H), 6.14 (t, J=4.0 Hz, 1H), 4.94 (d, J=4.0 Hz, 2H).LC/MS: m/z=397 [M+H]⁺ (Calc: 396);

(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-(4-(trifluoromethyl)phenyl)-2H-chromen-7-yl)pyrimidine-4-carboxamide(Compound 70): LC/MS: m/z=484 [M+H]⁺ (Calc: 483);

6-(((S)-1-amino-1-oxopropan-2-yl)amino)-2-((3R,4S)-3-hydroxy-4-(4-(trifluoromethyl)phenyl)chroman-7-yl)pyrimidine-4-carboxamide(Compound 71): ¹H NMR (400 MHz, MeOH-d₄): δ 8.04 (t, J=1.7 Hz, 1H),7.96-8.01 (m, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 7.16(s, 1H), 6.86 (dd, J=8.1, 2.6 Hz, 1H), 4.60 (br. s., 1H), 4.15-4.25 (m,2H), 4.11 (td, J=6.4, 2.1 Hz, 1H), 3.97-4.05 (m, 1H), 1.53 (d, J=7.3 Hz,3H). LC/MS: m/z=502 [M+H]⁺ (Calc: 501);

(S)-6-(((2-oxopyrrolidin-3-yl)amino)methyl)-2-(5-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)pyrimidine-4-carboxamide(Compound 72): ¹H NMR (400 MHz, MeOH-d₄): δ 8.41 (d, J=2.0 Hz, 1H), 8.35(dd, J=8.4, 2.0 Hz, 1H), 8.01 (s, 1H), 7.49 (d, J=8.8 Hz, 2H), 7.32 (d,J=8.4 Hz, 1H), 7.09 (d, J=8.8 Hz, 2H), 4.88 (d, J=16.5, 1H), 4.73 (d,J=16.5 Hz, 1H), 4.31 (dd, J=10.7, 8.7 Hz, 1H), 4.18 (t, J=5.8 Hz, 2H),4.04 (t, J=5.8 Hz, 2H), 3.40-3.59 (m, 2H), 2.62-2.80 (m, 1H), 2.21-2.39(m, 1H), 2.14 (quin, J=5.8 Hz, 2H). LC/MS: m/z=527 [M+H]⁺ (Calc: 526);

(S)-1-(6-(1-cyclohexyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)pyridin-2-yl)ethane-1,2-diol (Compound 73): ¹H NMR (400MHz, MeOH-d₄): δ 7.76-7.83 (m, 1H), 7.69-7.74 (m, 2H), 7.65 (d, J=7.8Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 6.99 (d, J=9.0 Hz, 1H), 4.82 (dd,J=6.6, 4.2 Hz, 1H), 3.94 (dd, J=11.2, 4.2 Hz, 1H), 3.76 (dd, J=11.2, 6.6Hz, 1H), 3.34-3.41 (m, 1H), 3.11 (br. s., 2H), 2.86 (br. s., 2H), 1.97(d, J=11.7 Hz, 2H), 1.87 (d, J=12.8 Hz, 2H), 1.72 (br. s., 5H), 1.59(qd, J=12.2, 2.9 Hz, 2H), 1.36-1.51 (m, 2H), 1.16-1.32 (m, 1H). LC/MS:m/z=367 [M+H]⁺ (Calc: 366);

(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(1-cyclohexyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)pyrimidine-4-carboxamide(Compound 74): ¹H NMR (400 MHz, MeOH-d₄): δ 8.14-8.23 (m, 2H), 7.05 (s,1H), 6.93 (d, J=9.0 Hz, 1H), 4.58 (br. s., 1H), 3.36-3.42 (m, 1H), 3.14(br. s., 2H), 2.88 (br. s., 2H), 1.96 (d, J=11.2 Hz, 2H), 1.88 (d,J=13.0 Hz, 2H), 1.73 (br. s., 5H), 1.56-1.66 (m, 2H), 1.53 (d, J=7.3 Hz,3H), 1.38-1.50 (m, 2H), 1.19-1.33 (m, 1H). LC/MS: m/z=437 [M+H]⁺ (Calc:436);

(S)-1-(6-(1-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)pyridin-2-yl)ethane-1,2-diol(Compound 75): ¹H NMR (400 MHz, MeOH-d₄): δ 7.81 (t, J=7.9 Hz, 1H),7.72-7.77 (m, 2H), 7.66 (d, J=7.7 Hz, 1H), 7.41 (d, J=7.7 Hz, 1H), 7.08(d, J=8.1 Hz, 1H), 4.82 (dd, J=6.6, 4.2 Hz, 1H), 3.99-4.08 (m, 2H), 3.94(dd, J=11.2, 4.2 Hz, 1H), 3.77 (dd, J=11.2, 6.6 Hz, 1H), 3.62 (dt,J=10.3, 5.3 Hz, 1H), 3.55 (td, J=11.3, 3.0 Hz, 2H), 3.10 (br. s., 2H),2.87 (br. s., 2H), 1.80-1.95 (m, 4H), 1.72 (br. s., 4H). LC/MS: m/z=369[M+H]⁺ (Calc: 368);

(S)-1-(6-(1-(4,4-difluorocyclohexyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)pyridin-2-yl)ethane-1,2-diol (Compound 76): ¹H NMR (400MHz, MeOH-d₄): δ 7.81 (t, J=7.9 Hz, 1H), 7.74-7.78 (m, 2H), 7.66 (d,J=7.7 Hz, 1H), 7.41 (d, J=7.7 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 4.82 (dd,J=6.6, 4.2 Hz, 1H), 3.94 (dd, J=11.2, 4.2 Hz, 1H), 3.77 (dd, J=11.2, 6.6Hz, 1H), 3.53-3.61 (m, 1H), 3.07 (br. s., 2H), 2.87 (br. s., 2H),2.08-2.20 (m, 2H), 1.86-2.05 (m, 6H), 1.72 (br. s., 4H). LC/MS: m/z=403[M+H]⁺ (Calc: 402);

(S)-5-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)benzyl)indolin-2-one (Compound 77): ¹H NMR (400 MHz, MeOH-d₄): δ 8.05 (s, 1H),7.91 (d, J=8.1 Hz, 1H), 7.80-7.86 (m, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.66(d, J=8.1 Hz, 2H), 7.56 (d, J=8.1 Hz, 2H), 7.46 (d, J=7.7 Hz, 1H), 6.94(d, J=8.1 Hz, 1H), 5.10 (s, 2H), 4.82 (dd, J=6.6, 4.2 Hz, 1H), 3.93 (dd,J=11.2, 4.2 Hz, 1H), 3.80 (s, 2H), 3.77 (dd, J=11.2, 6.6 Hz, 1H). LC/MS:m/z=429 [M+H]⁺ (Calc: 428);

(S)-1-(6-(1-((4-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-2-yl)ethane-1,2-diol(Compound 78): ¹H NMR (400 MHz, MeOH-d₄): δ 7.89 (d, J=1.3 Hz, 2H),7.82-7.88 (m, 5H), 7.79 (s, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.50 (d, J=7.7Hz, 1H), 4.83 (dd, J=6.6, 4.2 Hz, 1H), 3.89-3.97 (m, 3H), 3.77 (dd,J=11.2, 6.6 Hz, 1H), 2.57 (t, J=6.6 Hz, 2H), 1.72 (quin, J=6.3 Hz, 2H).LC/MS: m/z=479 [M+H]⁺ (Calc: 478);

tert-Butyl(S)-7-(4-((1-amino-1-oxopropan-2-yl)amino)-6-carbamoylpyrimidin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxylate (Compound 79); LC/MS: m/z=600 [M+H]⁺(Calc: 599);

(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-6-yl)pyrimidine-4-carboxamide(Compound 80): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.27 (s, 1H), 8.13 (d, J=8.8Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.07 (s, 1H),6.96 (d, J=8.6 Hz, 1H), 4.56 (br. d, J=5.9 Hz, 1H), 3.75 (t, J=5.7 Hz,2H), 2.93 (t, J=6.4 Hz, 2H), 2.09 (quin, J=6.1 Hz, 2H), 1.53 (d, J=7.0Hz, 3H). LC/MS: m/z=485 [M+H]⁺ (Calc: 484);

(S)-1-(6-(1-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-2-yl)ethane-1,2-diol(Compound 81): ¹H NMR (400 MHz, MeOH-d₄) δ: 7.75 (t, J=7.8 Hz, 1H), 7.67(d, J=2.1 Hz, 1H), 7.55-7.65 (m, 4H), 7.48 (d, J=8.0 Hz, 2H), 7.34 (d,J=7.6 Hz, 1H), 6.53 (d, J=8.6 Hz, 1H), 4.78 (dd, J=6.6, 4.2 Hz, 1H),4.67 (s, 2H), 3.91 (dd, J=11.2, 4.2 Hz, 1H), 3.74 (dd, J=11.2, 6.6 Hz,1H), 3.47-3.52 (m, 2H), 2.92 (t, J=6.0 Hz, 2H), 2.09 (quin, J=6.0 Hz,2H). LC/MS: m/z=429 [M+H]⁺ (Calc: 428);

(S)-6-((2-oxopyrrolidin-3-yl)oxy)-2-(5-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)pyrimidine-4-carboxamide(Compound 82): ¹H NMR (400 MHz, MeOH-d₄): δ 8.19-8.27 (m, 2H), 7.49 (d,J=8.8 Hz, 2H), 7.41 (s, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.08 (d, J=8.8 Hz,2H), 5.95 (t, J=8.4 Hz, 1H), 4.18 (t, J=5.7 Hz, 2H), 4.04 (t, J=5.7 Hz,2H), 3.47-3.58 (m, 2H), 2.82-2.94 (m, 1H), 2.23-2.40 (m, 1H), 2.15(quin, J=5.7 Hz, 2H). LC/MS: m/z=514 [M+H]⁺ (Calc: 513); and

In a similar manner,(2R,3S)-2,3-dihydroxy-3-(6-(5-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)pyridin-2-yl)propanamide (Compound 83) wasprepared. ¹H NMR (400 MHz, MeOH-d₄) δ: 7.89 (t, J=7.8 Hz, 1H), 7.82 (d,J=1.9 Hz, 1H), 7.73-7.79 (m, 2H), 7.58 (d, J=7.7 Hz, 1H), 7.47 (d, J=8.8Hz, 2H), 7.28 (d, J=8.3 Hz, 1H), 7.02 (d, J=8.8 Hz, 2H), 5.22 (d, J=1.4Hz, 1H), 4.65 (d, J=1.9 Hz, 1H), 4.15 (t, J=5.6 Hz, 2H), 4.01 (t, J=5.6Hz, 2H), 2.14 (quin, J=5.6 Hz, 2H). LC/MS: m/z=474 [M+H]⁺ (Calc: 473).

Example 11 Synthesis of6-(1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)picolinamide(Compound 84) and6-(4-methyl-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)picolinamide(Compound 85)

To a suspension of Compound 59 (0.183 g, 0.36 mmol) in DCM (5 mL) wasadded TFA (1 mL). The orange reaction mixture was stirred at RT for 3 hthen concentrated. The residue was dissolved in DCM and shakenvigorously with 1M aq. NaOH. The layers were separated and the aqueouslayer extracted with DCM. The combined organic extracts were dried overMgSO₄ and concentrated to give 0.140 g (95%) of Compound 84 as a whitesolid. Purification of a portion by flash chromatography (SiO₂, 0-4%(0.5% NH₄OH in MeOH) in DCM) provided an analytical sample. ¹H NMR (400MHz, DMSO-d₆): δ 8.43 (d, J=2.0 Hz, 1H), 8.39 (br s, 1H), 8.23 (dd,J=8.0, 2.0 Hz, 1H), 8.21 (d, J=8.4 Hz, 1H), 8.07 (t, J=8.0 Hz, 1H), 7.99(d, J=7.2 Hz, 1H), 7.73 (br s, 1H), 7.46 (d, J=8.6 Hz, 2H), 7.35 (d,J=8.0 Hz, 1H), 6.81 (d, J=8.6 Hz, 2H), 3.79 (br s, 4H), 2.97 (t, J=4.0Hz, 2H). LC/MS: m/z=413 [M+H]⁺ (Calc: 412).

To a suspension of Compound 84 (0.080 g, 0.19 mmol) in DCE (3 mL) andDCM (1 mL) was added 37% aq. formaldehyde (0.043 mL, 0.58 mmol) followedby NaBH(OAc)₃ (0.123 g, 0.58 mmol). The reaction mixture was stirred atRT for 1 h then 1M aq. NaOH (5 mL) and DCM (5 mL) were added. Themixture was stirred vigorously for 15 min, the layers separated and theaqueous layer extracted with DCM. The combined organic extracts weredried over MgSO₄, concentrated and the residue was purified by flashchromatography (SiO₂, 0-8% (0.5% NH₄OH in MeOH) in DCM) to give 0.072 g(87%) of Compound 85 as an off-white solid. ¹H NMR (400 MHz, MeOH-d₄): δ8.27 (d, J=2.0 Hz, 1H), 8.15 (dd, J=8.4, 2.0 Hz, 1H), 8.12-8.02 (m, 3H),7.43 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.0 Hz, 1H), 6.87 (d, J=8.8 Hz, 2H),3.92 (br s, 2H), 3.77 (s, 2H), 2.96 (t, J=4.4 Hz, 2H), 2.45 (s, 3H).LC/MS: m/z=427 [M+H]⁺ (Calc: 426).

In a similar manner the following compounds were prepared:

(S)-1-(6-(1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyridin-2-yl)ethane-1,2-diol (Compound 86): LC/MS:m/z=430 [M+H]⁺ (Calc: 429);

(S)-1-(6-(4-(cyclopropylmethyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyridin-2-yl)ethane-1,2-diol(Compound 87): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.14 (d, J=2.0 Hz, 1H), 8.05(dd, J=8.0, 2.0 Hz, 1H), 7.88 (t, J=8.0 Hz, 1H), 7.80 (d, J=7.6 Hz, 1H),7.52 (d, J=7.6 Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.0 Hz, 1H),6.86 (d, J=8.8 Hz, 2H), 4.84 (dd, J=6.4, 4.0 Hz, 1H), 3.96 (dd, J=11.2,4.0 Hz, 1H), 3.90 (br s, 2H), 3.87 (s, 2H), 3.79 (dd, J=11.2, 6.4 Hz,1H), 3.11 (t, J=4.0 Hz, 2H), 2.46 (d, J=6.8 Hz, 2H), 1.02-0.92 (m, 1H),0.62-0.55 (m, 2H), 0.21-0.14 (m, 2H). LC/MS: m/z=484 [M+H]⁺ (Calc: 483);

(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyrimidine-4-carboxamide(Compound 88): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.61 (d, J=1.8 Hz, 1H), 8.51(dd, J=8.1, 1.8 Hz, 1H), 7.44 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.1 Hz, 1H),7.19 (s, 1H), 6.86 (d, J=8.8 Hz, 2H), 4.60 (br. d, J=6.4 Hz, 1H), 3.92(s, 4H), 3.13 (t, J=4.6 Hz, 2H), 1.55 (d, J=7.3 Hz, 3H). LC/MS: m/z=500[M+H]⁺ (Calc: 499);

(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-(cyclopropylmethyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyrimidine-4-carboxamide (Compound 89): ¹H NMR(400 MHz, MeOH-d₄) δ: 8.60 (d, J=1.8 Hz, 1H), 8.50 (dd, J=8.3, 1.8 Hz,1H), 7.43 (d, J=8.8 Hz, 2H), 7.31 (d, J=8.1 Hz, 1H), 7.17 (s, 1H), 6.87(d, J=8.8 Hz, 2H), 4.59 (br. d, J=6.6 Hz, 1H), 3.87 (br. s., 4H), 3.11(br. s., 2H), 2.48 (d, J=6.4 Hz, 2H), 1.54 (d, J=7.0 Hz, 3H), 0.93-1.04(m, 1H), 0.55-0.65 (m, 2H), 0.15-0.22 (m, 2H). LC/MS: m/z=554 [M+H]⁺(Calc: 553); and

(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-methyl-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyrimidine-4-carboxamide (Compound 90): ¹H NMR(400 MHz, MeOH-d₄) δ: 8.62 (d, J=2.0 Hz, 1H), 8.52 (dd, J=8.1, 2.0 Hz,1H), 7.45 (d, J=8.8 Hz, 2H), 7.33 (d, J=8.1 Hz, 1H), 7.19 (s, 1H), 6.88(d, J=8.8 Hz, 2H), 4.60 (br. d, J=6.6 Hz, 1H), 3.92 (br. s., 2H), 3.76(s, 2H), 2.94 (t, J=4.5 Hz, 2H), 2.44 (s, 3H), 1.56 (d, J=7.3 Hz, 3H).LC/MS: m/z=514 [M+H]⁺ (Calc: 513).

Example 12 Synthesis of6-(4-acetyl-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)picolinamide(Compound 91)

To a solution of Compound 84 (0.070 g, 0.17 mmol) in DCM (3 mL) wasadded TEA (0.035 mL, 0.25 mmol) followed by AcCl (0.013 mL, 0.19 mmol).The reaction mixture was stirred at RT for 30 min during which time athick white precipitate formed. The reaction mixture was diluted withDCM and washed with water. The aqueous layer was extracted with DCM andthe combined organic extracts were dried over MgSO₄, concentrated andthe residue purified by flash chromatography (SiO₂, 0-8% (0.5% NH₄OH inMeOH) in DCM) to give 0.057 g (74%) of Compound 91 as a white solid. ¹HNMR (400 MHz, DMSO-d₆) (mixture of rotamers): δ 8.55 (d, J=2.0 Hz,0.5H), 8.42 (d, J=2.0 Hz, 0.5H), 8.38 (br s, 1H), 8.29 (dd, J=8.4, 2.0Hz, 0.5H), 8.24-8.18 (m, 1.5H), 8.11-8.05 (m, 1H), 8.00 (d, J=7.2 Hz,0.5H), 7.99 (d, J=7.2 Hz, 0.5H), 7.77 (br s, 0.5H), 7.75 (br s, 0.5H),7.50 (t, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 0.5H), 7.31 (d, J=8.4 Hz,0.5H), 6.92 (d, J=8.4 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 4.62 (br s, 1H),4.58 (br s, 1H), 4.00 (br s, 1H), 3.89 (br s, 1H), 3.76 (br s, 1H), 3.72(t, J=4.6 Hz, 1H), 2.08 (s, 1.5H), 1.77 (s, 1.5H). LC/MS: m/z=455 [M+H]⁺(Calc: 454).

In a similar manner the following compounds were prepared:

7-(6-Carbamoylpyridin-2-yl)-N,N-diethyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxamide(Compound 92): ¹H NMR (400 MHz, MeOH-d₄): δ 8.28 (d, J=2.0 Hz, 1H),8.14-8.02 (m, 4H), 7.45 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 1H), 7.03(d, J=8.4 Hz, 2H), 4.54 (s, 2H), 4.09 (br s, 2H), 3.64 (t, J=5.2 Hz,2H), 3.12 (q, J=7.2 Hz, 4H), 0.98 (t, J=7.2 Hz, 6H). LC/MS: m/z=512[M+H]⁺ (Calc: 511);

6-(4-(Cyclopropanecarbonyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)picolinamide(Compound 93): ¹H NMR (400 MHz, MeOH-d₄) (mixture of rotamers): δ 8.45(d, J=1.6 Hz, 0.5H), 8.35 (d, J=1.6 Hz, 0.5H), 8.21-8.03 (m, 4H), 7.48(d, J=8.4 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.0 Hz, 0.5H),7.36 (d, J=8.0 Hz, 0.5H), 6.98-6.92 (m, 2H), 4.91 (br s, 1H), 4.68 (brs, 1H), 4.11 (br s, 2H), 3.95 (br s, 2H), 2.23-2.17 (m, 0.5H), 1.86-1.80(m, 0.5H), 0.84-0.78 (m, 2H), 0.74-0.63 (m, 2H). LC/MS: m/z=481 [M+H]⁺(Calc: 480);

(S)-1-(1-cyclohexyl-7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)ethan-1-one(Compound 94): ¹H NMR (400 MHz, MeOH-d₄): δ 7.76-7.92 (m, 3H), 7.68 (d,J=7.8 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.02 (d, J=8.6 Hz, 0.4H), 6.98(d, J=8.6 Hz, 0.6H), 4.82 (dd, J=6.4, 4.4 Hz, 1H), 4.73 (s, 1.2H), 4.68(s, 0.8H), 3.94 (dd, J=11.2, 4.4 Hz, 1H), 3.63-3.82 (m, 3H), 3.34-3.55(m, 3H), 2.12 (s, 1.8H), 2.11 (s, 1.2H), 1.83-2.04 (m, 4H), 1.68-1.78(m, 1H), 1.38-1.65 (m, 5H), 1.22-1.37 (m, 1H). LC/MS: m/z=410 [M+H]⁺(Calc: 409);

(S)-1-(6-(4-(methylsulfonyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyridin-2-yl)ethane-1,2-diol(Compound 95): ¹H NMR (400 MHz, MeOH-d₄): δ 8.20 (d, J=1.8 Hz, 1H), 8.11(dd, J=8.1, 1.8 Hz, 1H), 7.91 (t, J=7.7 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H),7.54 (d, J=7.5 Hz, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.40 (d, J=8.1 Hz, 1H),6.90 (d, J=8.6 Hz, 2H), 4.84-4.88 (m, 1H), 4.45 (br. s., 2H), 4.02 (br.s., 2H), 3.98 (dd, J=11.2, 4.2 Hz, 1H), 3.80 (dd, J=11.2, 6.6 Hz, 1H),3.71 (br. s., 2H), 2.84 (s, 3H). LC/MS: m/z=508 [M+H]⁺ (Calc: 507);

(S)-1-(7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)ethan-1-one(Compound 96): ¹H NMR (400 MHz, MeOH-d₄): δ 8.24 (d, J=1.8 Hz, 0.5H),8.19 (d, J=1.8 Hz, 0.5H), 8.07 (dd, J=8.4, 2.0 Hz, 0.5H), 8.04 (dd,J=8.1, 2.0 Hz, 0.5H), 7.86-7.95 (m, 1H), 7.78-7.86 (m, 1H), 7.53 (t,J=7.4 Hz, 1H), 7.44-7.50 (m, 2H), 7.38 (d, J=8.4 Hz, 0.5H), 7.33 (d,J=8.1 Hz, 0.5H), 6.89-6.97 (m, 2H), 4.83-4.86 (m, 1H), 4.66 (s, 1H),4.62 (br. s, 1H), 4.03 (br. s., 1H), 3.97 (dd, J=11.2, 4.2 Hz, 1H), 3.93(br. s., 2H), 3.84-3.89 (m, 1H), 3.75-3.84 (m, 1H), 2.21 (s, 1.5H), 1.94(s, 1.5H). LC/MS: m/z=472 [M+H]⁺ (Calc: 471);

(S)-7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-N-ethyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxamide(Compound 97): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.24 (d, J=2.0 Hz, 1H), 8.04(dd, J=8.1, 2.0 Hz, 1H), 7.90 (t, J=7.9 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H),7.53 (d, J=7.7 Hz, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.33 (d, J=8.4 Hz, 1H),6.90 (d, J=8.8 Hz, 2H), 4.85 (dd, J=6.6, 4.2 Hz, 1H), 4.50 (s, 2H), 3.97(dd, J=11.2, 4.2 Hz, 1H), 3.90 (br. s., 2H), 3.80 (dd, J=11.2, 6.6 Hz,1H), 3.75 (br. s., 2H), 3.12 (q, J=7.2 Hz, 2H), 1.02 (t, J=7.2 Hz, 3H).LC/MS: m/z=501 [M+H]⁺ (Calc: 500);

(S)-7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxamide(Compound 98): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.24 (d, J=1.8 Hz, 1H), 8.06(dd, J=8.3, 2.0 Hz, 1H), 7.90 (t, J=7.7 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H),7.53 (d, J=7.5 Hz, 1H), 7.46 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.1 Hz, 1H),6.90 (d, J=8.8 Hz, 2H), 4.85 (dd, J=6.6, 4.2 Hz, 1H), 4.50 (s, 2H), 3.97(dd, J=11.2, 4.2 Hz, 1H), 3.91 (br. s., 2H), 3.81 (dd, J=11.2, 6.6 Hz,1H), 3.76 (br. s., 2H). LC/MS: m/z=473 [M+H]⁺ (Calc: 472);

(S)-1-(7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2-hydroxyethan-1-one(Compound 99): ¹H NMR (400 MHz, MeOH-d₄) δ: (mixture of rotamers) 8.22(s, 1H), 8.01-8.12 (m, 1H), 7.87-7.96 (m, 1H), 7.78-7.86 (m, 1H), 7.54(t, J=6.7 Hz, 1H), 7.47 (dd, J=8.5, 5.0 Hz, 2H), 7.38 (d, J=8.4 Hz,0.4H), 7.34 (d, J=8.4 Hz, 0.6H), 6.92 (d, J=8.8 Hz, 2H), 4.82-4.88 (m,1H), 4.64 (br. s., 1.2H), 4.56 (s, 0.8H), 4.40 (s, 0.8H), 4.09 (s,1.2H), 3.89-4.06 (m, 3.8H), 3.77-3.84 (m, 1H), 3.74 (br. t, J=4.6 Hz,1.2H). LC/MS: m/z=488 [M+H]⁺ (Calc: 487);

(S)-1-(7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2-(dimethylamino)ethan-1-one(Compound 100): ¹H NMR (400 MHz, MeOH-d₄) δ: (mixture of rotamers) 8.25(s, 0.4H), 8.20 (s, 0.6H), 8.05 (d, J=8.1 Hz, 1H), 7.86-7.97 (m, 1H),7.78-7.85 (m, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.43-7.50 (m, 2H), 7.37 (d,J=8.4 Hz, 0.4H), 7.34 (d, J=8.4 Hz, 0.6H), 6.93 (d, J=8.6 Hz, 2H), 4.86(t, J=5.2 Hz, 1H), 4.75 (br. s., 0.8H), 4.63 (br. s., 1.2H), 4.04 (br.s., 1H), 3.85-4.01 (m, 4H), 3.76-3.84 (m, 1H), 3.36 (s, 0.8H), 3.00 (s,1.2H), 2.29 (s, 2.4H), 2.16 (s, 3.6H). LC/MS: m/z=515 [M+H]⁺ (Calc:514);

(S)-1-(6-(1-isobutyl-4-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo-[e][1,4]diazepin-7-yl)pyridin-2-yl)ethane-1,2-diol(Compound 124): LC/MS: m/z=420.1 [M+H]⁺ (Calc: 419.2); and

(2R,3S)-2,3-dihydroxy-3-(6-(1-isobutyl-4-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyridin-2-yl)propanamide(Compound 125): LC/MS: m/z=463.2 [M+H]⁺ (Calc: 462.2).

Example 13 Synthesis of6-(4-(cyanomethyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)picolinamide(Compound 102)

To a solution of Compound 84 (0.100 g, 0.24 mmol) in ACN (2 mL) and THF(1 mL) was added DIPEA (0.13 mL, 0.73 mmol) followed by Compound 101(0.020 mL, 0.29 mmol). The reaction mixture was stirred at RT overnight,quenched with water and extracted with EtOAc. The combined organicextracts were dried over MgSO₄ and concentrated. The residue waspurified by flash chromatography (SiO₂, 0-5% MeOH/DCM) to give 0.090 g(82%) of Compound 102 as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ8.43 (d, J=2.0 Hz, 1H), 8.35 (br s, 1H), 8.27 (dd, J=8.4, 2.0 Hz, 1H),8.19 (d, J=7.6, 1H), 8.09 (t, J=8.0 Hz, 1H), 8.00 (d, J=6.8 Hz, 1H),7.79 (br s, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.0 Hz, 1H), 6.89(d, J=8.8 Hz, 2H), 3.92 (br s, 2H), 3.87 (s, 2H), 3.76 (br s, 2H), 2.94(t, J=4.0 Hz, 2H). LC/MS: m/z=452 [M+H]⁺ (Calc: 451).

In a similar manner the following compounds were prepared:

(S)-2-(7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)acetamide(Compound 103): ¹H NMR (400 MHz, MeOH-d₄): δ 8.09-8.03 (m, 2H), 7.90 (t,J=8.0 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.44 (d,J=8.8 Hz, 2H), 7.38 (d, J=8.0 Hz, 1H), 6.87 (d, J=8.8 Hz, 2H), 4.90-4.84(m, 1H), 3.97 (dd, J=11.2, 4.4 Hz, 1H), 3.90 (br s, 2H), 3.88 (s, 2H),3.80 (dd, J=11.2, 6.8 Hz, 1H), 3.18 (s, 2H), 3.11 (br. s, 2H). LC/MS:m/z=487 [M+H]⁺ (Calc: 486);

(S)-2-(1-cyclohexyl-7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)acetamide(Compound 104): ¹H NMR (400 MHz, MeOH-d₄): δ 7.85 (dd, J=8.5, 2.1 Hz,1H), 7.77-7.83 (m, 2H), 7.67 (d, J=7.9 Hz, 1H), 7.41 (d, J=7.5 Hz, 1H),7.07 (d, J=8.5 Hz, 1H), 4.81 (dd, J=6.6, 4.2 Hz, 1H), 3.93 (dd, J=11.2,4.2 Hz, 1H), 3.88 (s, 2H), 3.76 (dd, J=11.2, 6.6 Hz, 1H), 3.42 (t,J=11.2 Hz, 1H), 3.19 (s, 2H), 3.17 (br. s, 2H), 2.87-2.94 (m, 2H), 2.00(d, J=11.2 Hz, 2H), 1.90 (d, J=12.3 Hz, 2H), 1.73 (d, J=13.0 Hz, 1H),1.40-1.67 (m, 4H), 1.18-1.37 (m, 1H). LC/MS: m/z=425 [M+H]⁺ (Calc: 424);

(S)-2-(7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-N-methylacetamide(Compound 105): ¹H NMR (400 MHz, MeOH-d₄): δ 8.04-8.09 (m, 2H), 7.90 (t,J=7.9 Hz, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.53 (d, J=7.5 Hz, 1H), 7.44 (d,J=8.8 Hz, 2H), 7.38 (d, J=8.4 Hz, 1H), 6.87 (d, J=8.8 Hz, 2H), 4.86 (dd,J=6.7, 4.2 Hz, 1H), 3.97 (dd, J=11.2, 4.2 Hz, 1H), 3.89 (br. s, 2H),3.86 (s, 2H), 3.79 (dd, J=11.2, 6.7 Hz, 1H), 3.18 (s, 2H), 3.08 (br. s.,2H), 2.79 (s, 3H). LC/MS: m/z=501 [M+H]⁺ (Calc: 500);

(S)-2-(7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)acetonitrile(Compound 106): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.16 (d, J=2.0 Hz, 1H),8.06 (dd, J=8.3, 2.0 Hz, 1H), 7.90 (t, J=7.7 Hz, 1H), 7.81 (d, J=7.5 Hz,1H), 7.53 (d, J=7.7 Hz, 1H), 7.46 (d, J=8.8 Hz, 2H), 7.36 (d, J=8.1 Hz,1H), 6.89 (d, J=8.8 Hz, 2H), 4.84-4.87 (m, 1H), 3.97 (dd, J=11.2, 4.2Hz, 1H), 3.91-4.01 (br. s., 2H), 3.84 (s, 2H), 3.77-3.83 (m, 3H), 3.07(br. t, J=4.5 Hz, 2H). LC/MS: m/z=469 [M+H]⁺ (Calc: 468); and

(S)-1-(6-(4-((1H-imidazol-2-yl)methyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyridin-2-yl)ethane-1,2-diol(Compound 107): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.05 (dd, J=8.1, 1.8 Hz,1H), 8.01 (s, 1H), 7.90 (t, J=7.7 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.53(d, J=7.5 Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.1 Hz, 1H), 7.02(s, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.83-4.86 (m, 1H), 3.97 (dd, J=11.2,4.2 Hz, 1H), 3.91 (br. s., 2H), 3.82 (s, 2H), 3.75-3.80 (m, 3H), 3.00(br. s., 2H)¹H NMR (400 MHz, MeOH-d₄) δ: 8.24 (d, J=2.0 Hz, 1H), 8.04(dd, J=8.1, 2.0 Hz, 1H), 7.90 (t, J=7.9 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H),7.53 (d, J=7.7 Hz, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.33 (d, J=8.4 Hz, 1H),6.90 (d, J=8.8 Hz, 2H), 4.85 (dd, J=6.6, 4.2 Hz, 1H), 4.50 (s, 2H), 3.97(dd, J=11.2, 4.2 Hz, 1H), 3.90 (br. s., 2H), 3.80 (dd, J=11.2, 6.6 Hz,1H), 3.75 (br. s., 2H), 3.12 (q, J=7.2 Hz, 2H), 1.02 (t, J=7.2 Hz, 3H).LC/MS: m/z=510 [M+H]⁺ (Calc: 509).

Example 14 Synthesis of6-(4-(2,3-dihydroxypropyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)picolinamide(Compound 109)

To a solution of Compound 84 (0.140 g, 0.34 mmol) in THF (2 mL) wasadded DIPEA (0.18 mL, 1.02 mmol) followed by allyl bromide (0.035 mL,0.41 mmol). The reaction mixture was stirred at RT overnight, quenchedwith water and extracted with EtOAc. The combined organic extracts weredried over MgSO₄ and concentrated. The residue was purified by flashchromatography (SiO₂, 0-5% MeOH/DCM) to give 0.123 g (80%) of Compound108 as a white solid. LC/MS: m/z=453 [M+H]⁺ (Calc: 452).

To a solution of Compound 108 (0.060 g, 0.13 mmol) in THF (2 mL) andwater (0.5 mL) was added osmium tetroxide (2.5% solution in t-BuOH, 0.17mL, 0.013 mmol) followed by NMO (0.023 g, 0.20 mmol). The reactionmixture was stirred at RT overnight then quenched with satd. aq. NaHCO₃and extracted with EtOAc. The combined organic extracts were dried overMgSO₄ and concentrated. The residue was purified two times by flashchromatography (SiO₂, 0-10% (0.5% NH₄OH in MeOH) in DCM) to give 0.026 g(40%) of Compound 109 as a white solid. ¹H NMR (400 MHz, MeOH-d₄): δ8.29 (d, J=1.6 Hz, 1H), 8.19 (dd, J=8.0, 2.0 Hz, 1H), 8.15 (dd, J=7.2,1.6 Hz, 1H), 8.10-8.04 (m, 2H), 7.44 (d, J=8.8 Hz, 2H), 7.39 (d, J=7.6Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 3.96-3.85 (m, 3H), 3.93 (s, 2H), 3.54(sept, J=5.6 Hz, 2H), 3.16-3.09 (m, 2H), 2.68 (dd, J=13.2, 4.0 Hz, 1H),2.56 (dd, J=13.2, 8.0 Hz, 1H). LC/MS: m/z=487 [M+H]⁺ (Calc: 486).

Example 15 Synthesis of6-(4-(4-(trifluoromethyl)phenyl)chroman-7-yl)picolinamide (Compound 110)

To a solution of Compound 69 (0.154 g, 0.389 mmol) in MeOH (15 mL) wasadded 10% Pd/C (0.041 g). The reaction mixture was stirred under 1 atm.of hydrogen for 20 h. The mixture was filtered through Celite, thefiltrate concentrated and the residue purified by flash chromatography(SiO₂, 40-70% EtOAc/hexanes) to give 0.131 g (85%) of Compound 110 as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.28 (br. s., 1H), 8.11 (dd,J=7.9, 1.0 Hz, 1H), 8.03 (t, J=7.7 Hz, 1H), 7.97 (dd, J=7.5, 1.0 Hz,1H), 7.80 (d, J=1.8 Hz, 1H), 7.69-7.74 (m, 3H), 7.68 (br. s., 1H), 7.42(d, J=8.1 Hz, 2H), 6.85 (d, J=8.1 Hz, 1H), 4.44 (t, J=6.5 Hz, 1H),4.14-4.28 (m, 2H), 2.26-2.38 (m, 1H), 2.03-2.14 (m, 1H). LC/MS: m/z=399[M+]⁺ (Calc: 398).

In a similar manner the following compounds were prepared:

6-(((S)-1-amino-1-oxopropan-2-yl)amino)-2-(4-(4-(trifluoromethyl)phenyl)chroman-7-yl)pyrimidine-4-carboxamide (Compound 111): ¹H NMR (400 MHz,DMSO-d₆): δ 8.23 (br. s., 1H), 7.98-8.01 (m, 1H), 7.97 (d, J=7.9 Hz,1H), 7.91 (br. d, J=6.4 Hz, 1H), 7.67-7.75 (m, 3H), 7.52 (br. d, J=4.6Hz, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.11 (s, 1H), 6.97 (br. d, J=6.8 Hz,1H), 6.79 (d, J=8.1 Hz, 1H), 4.50-4.62 (m, 1H), 4.44 (t, J=6.5 Hz, 1H),4.09-4.28 (m, 2H), 2.23-2.39 (m, 1H), 1.96-2.15 (m, 1H), 1.37 (d, J=6.8Hz, 3H). LC/MS: m/z=486 [M+H]⁺ (Calc: 485); and

6-(((S)-1-amino-1-oxopropan-2-yl)amino)-2-(4-(4-fluorobenzyl)chroman-7-yl)pyrimidine-4-carboxamide(Compound 112): ¹H NMR (400 MHz, MeOH-d₄): δ 7.95-8.00 (m, 1H), 7.90 (s,1H), 7.30 (m, 2H), 7.25 (m, 2H), 7.05 (m, 2H), 4.60 (m, 1H), 4.20 (m,2H), 3.20 (m, 2H), 2.80 (m, 1H), 1.70-2.00 (m, 2H), 1.55 (m, 3H). LC/MS:m/z=500 [M+H]⁺ (Calc: 499).

Example 16 Synthesis of(S)-6-(4-(cyclopropylmethyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)-4-(1,2-dihydroxyethyl)picolinamide(Compound 122)

To a solution of Compound 30 (900 mg, 1.73 mmol) and4,6-dichloropicolinonitrile (Compound 113) (300 mg, 1.73 mmol) in DME(12 mL) and EtOH (4 mL) was added Pd(PPh₃)₂Cl₂ (61 mg, 0.087 mmol)followed by 2.0M aq. Na₂CO₃ (2.60 mL, 5.20 mmol). The reaction mixturewas purged with nitrogen and stirred at RT for 6 h. A very thick whiteprecipitate had formed. The reaction was diluted with water andextracted with EtOAc (2×). The combined organic extracts were dried overMgSO₄ and concentrated. The residue was purified by flash chromatography(SiO₂, 10-20% EtOAc/hexanes) to afford first Compound 114 as a lightyellow solid (303 mg; Yield 33%) followed by Compound 115 as a lightyellow solid (364 mg; Yield 40%). Compound 114: LC/MS: m/z=551/553[M+Na]⁺ (Calc: 529). Compound 115: LC/MS: m/z=551/553 [M+Na]⁺ (Calc:529).

To a solution of Compound 114 (303 mg, 0.573 mmol) in DCM (10 mL) wasadded TFA (2 mL). The reaction mixture was stirred at RT for 2.5 h thenconcentrated. The residue was dissolved in DCM and shaken vigorouslywith 1.0M aq. NaOH for 5 min. The aqueous layer was extracted with DCM(2×). The combined organic extracts were dried over MgSO₄ andconcentrated to afford Compound 116 as a yellow powder which was usedwithout further purification (243 mg). Yield 99%. ¹H NMR (400 MHz,CDCl₃) δ: 8.03 (d, J=2.0 Hz, 1H), 7.96 (d, J=1.8 Hz, 1H), 7.93 (dd,J=8.1, 2.0 Hz, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.39(d, J=8.1 Hz, 1H), 6.79 (d, J=8.8 Hz, 2H), 3.98 (s, 2H), 3.84 (br. s.,2H), 3.18 (t, J=4.7 Hz, 2H). LC/MS: m/z=429/431 [M+H]⁺ (Calc: 428).

To a solution of Compound 116 (240 mg, 0.56 mmol) in DCE (5 mL) wasadded cyclopropanecarbaldehyde (Compound 117) (43 mg, 0.62 mmol)followed by sodium triacetoxyborohydride (178 mg, 0.84 mmol). Thereaction mixture was stirred at RT for 1 h then quenched with satd. aq.NaHCO₃, diluted with water and extracted with DCM (2×). The combinedorganic extracts were dried over MgSO₄ and concentrated. The residue waspurified by flash chromatography (SiO₂, 40-60% EtOAc/hexanes) to isolateCompound 118 as a light yellow foam (230 mg). Yield 85%. ¹H NMR (400MHz, CDCl₃) δ: 8.03 (d, J=2.2 Hz, 1H), 7.90-7.98 (m, 2H), 7.63 (d, J=1.8Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H), 6.81 (d, J=8.8Hz, 2H), 3.88 (s, 2H), 3.83 (br. s., 2H), 3.05-3.12 (m, 2H), 2.44 (d,J=6.4 Hz, 2H), 0.88-1.01 (m, 1H), 0.55-0.64 (m, 2H), 0.10-0.19 (m, 2H).LC/MS: m/z=483/485 [M+H]⁺ (Calc: 482).

In a 15 mL pressure tube, Compound 118 (220 mg, 0.45 mmol) was dissolvedin THF (4 mL). Then added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Compound 119) (0.10 mL,0.59 mmol), TBAF (1.0M in THF, 0.91 mL, 0.91 mmol), and Pd(dppf)Cl₂CH₂Cl₂ adduct (19 mg, 0.023 mmol). The reaction was purged with nitrogenthen the tube was sealed and heated at 85° C. for 2 h. After cooling toRT, the mixture was partioned between water and EtOAc. The aqueous layerwas extracted with EtOAc. The combined organics were dried over MgSO₄and concentrated. The residue was purified by flash chromatography(SiO₂, 0% to 5% MeOH/DCM) to give Compound 120 as a light orange foamysolid (173 mg). Yield 80%. ¹H NMR (400 MHz, CDCl₃) δ: 8.04 (d, J=2.0 Hz,1H), 7.95 (dd, J=8.4, 2.0 Hz, 1H), 7.86 (d, J=1.1 Hz, 1H), 7.65 (d,J=1.1 Hz, 1H), 7.42 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.1 Hz, 1H), 6.79 (d,J=8.8 Hz, 2H), 6.76 (dd, J=17.6, 10.8 Hz, 1H), 6.13 (d, J=17.6 Hz, 1H),5.69 (d, J=10.8 Hz, 1H), 3.88 (s, 2H), 3.83 (br. s., 2H), 3.07-3.13 (m,2H), 2.44 (d, J=6.4 Hz, 2H), 0.88-1.00 (m, 1H), 0.55-0.62 (m, 2H),0.10-0.17 (m, 2H). LC/MS: m/z=475 [M+H]⁺ (Calc: 474).

To a partial suspension of Compound 120 (170 mg, 0.36 mmol) in t-BuOH (6mL) and water (6 mL) was added AD-mix-alpha (500 mg; 1.4 g/mmol of vinylsubstrate). The reaction mixture was stirred vigorously at RT for 24 hthen diluted with water and extracted with EtOAc (2×). The combinedorganics were washed with water and brine then dried over MgSO₄ andconcentrated. The residue was purified by flash chromatography (SiO₂,0-10% MeOH/DCM) to isolate Compound 121 as an off-white foamy solid (98mg). Yield 54%. ¹H NMR (400 MHz, MeOH-d₄) δ: 8.18-8.24 (m, 2H), 8.09(dd, J=8.4, 2.2 Hz, 1H), 7.83 (s, 1H), 7.44 (d, J=8.8 Hz, 2H), 7.38 (d,J=8.4 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 4.81-4.85 (m, 1H), 3.88 (s, 4H),3.71-3.79 (m, 2H), 3.10 (br. t, J=4.3 Hz, 2H), 2.47 (d, J=6.6 Hz, 2H),0.93-1.03 (m, 1H), 0.55-0.63 (m, 2H), 0.15-0.23 (m, 2H). LC/MS: m/z=509[M+H]⁺ (Calc: 508).

To a solution of Compound 121 (98 mg, 0.19 mmol) in EtOH (5 mL) andwater (0.5 mL) was added hydrido(dimethylphosphinous acid-kP)[hydrogenbis(dimethylphosphinito-kP)]platinum(II) (8 mg, 0.019 mmol, Strem). Thereaction mixture was stirred at 85° C. for 2 h then cooled to RT andconcentrated. The residue was purified twice by flash chromatography(SiO₂, 0-10% MeOH/DCM) to isolate a viscous oil. The oil was dissolvedin ACN/water and lyophilized to afford Compound 122 as a pale yellowsolid (32 mg). Yield 32%. ¹H NMR (400 MHz, MeOH-d₄) δ: 8.30 (d, J=2.0Hz, 1H), 8.20 (dd, J=8.4, 2.0 Hz, 1H), 8.15 (s, 1H), 8.12 (s, 1H), 7.44(d, J=8.8 Hz, 2H), 7.38 (d, J=8.4 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H),4.84-4.89 (m, 1H), 3.89 (br. s., 4H), 3.75 (tt, J=11.5, 5.6 Hz, 2H),3.12 (br. s., 2H), 2.49 (d, J=6.6 Hz, 2H), 0.94-1.04 (m, 1H), 0.55-0.63(m, 2H), 0.15-0.24 (m, 2H). LC/MS: m/z=527 [M+H]⁺ (Calc: 526).

In a similar manner (S)-4-(4-(cyclopropylmethyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)-6-(1,2-dihydroxyethyl)picolinamide (Compound 123) was prepared. ¹H NMR (400 MHz, MeOH-d₄) δ:8.33 (d, J=1.8 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.91 (d, J=2.0 Hz, 1H),7.83 (dd, J=8.1, 2.0 Hz, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.4 Hz,1H), 6.89 (d, J=8.8 Hz, 2H), 4.90 (dd, J=6.2, 4.6 Hz, 1H), 3.81-3.97 (m,6H), 3.08-3.14 (m, 2H), 2.48 (d, J=6.6 Hz, 2H), 0.93-1.03 (m, 1H),0.56-0.63 (m, 2H), 0.15-0.22 (m, 2H). LC/MS: m/z=527 [M+H]⁺ (Calc: 526).

In the foregoing Examples the following abbreviations are used:

ACN acetonitrile AcCl acetyl chloride AcOH acetic acid aq. aqueous atmatmosphere(s) BINAP 2,2′-bis(diphenylphosphanyl)-1,1′-binaphthyl Bnbenzyl Boc tert-butoxycarbonyl Boc₂O di-tert-butyl dicarbonate Bzbenzoyl ° C. degrees Celcius conc. concentrated DCE 1,2-dichloroethaneDCM dichloromethane DIPEA diisopropylethylamine DME 1,2-dimethoxyethaneDMF dimethylformamide DMSO dimethylsulfoxide Et₂O diethyl ether EtOAcethyl acetate EtOH ethanol h hour(s) HPLC high pressure liquidchromatography i-PrOH iso-propanol MeOH methanol min minute(s) Msmethanesulfonyl MsCl methanesulfonyl chloride NBS N-bromosuccinimidePd/C palladium on carbon Pd(dppf)Cl₂[1,1′-bis(diphenylphosphino)ferrocene] palladium(II) dichloridePd(PPh₃)₂Cl₂ bis(triphenylphosphine)palladium(II) dichloride PPh₃triphenylphosphine psi pounds per square inch RT room temperature satd.saturated t-BuOH tert-butyl alcohol TEA triethylamine Tftrifluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuran

Example 17

Representative Compounds of the Disclosure have been tested in theFLIPR® or FLIPR^(TETRA)® assay and/or EP assays for sodium channelblocking activity. The assays are described in detail above.

Representative values obtained from the assays are presented in TABLE 3.

TABLE 3 Evaluation of compounds as sodium channel (Na_(v)) blockersNa_(v)1.7 Activity (μM) Na_(v)1.7 Activity (μM) FLIPR assay EP assayCompound IC₅₀ K_(i)  58 0.357 ± 0.015  61 0.404 ± 0.036  62 0.419 ±0.058 0.458 ± 0.078  63 0.246 ± 0.029 0.344 ± 0.100  64 1.038 ± 0.077 65 0.338 ± 0.034  66 0.913 ± 0.024  67 >20  68 >20  69 0.524 ± 0.077 71 >20  72 0.110 ± 0.022  73 0.331 ± 0.031  74 4.885 ± 0.470  75 3.346± 0.244  76 0.526 ± 0.034  77 7.795 ± 0.691  78 0.857 ± 0.103  80 0.653± 0.118  81 0.091 ± 0.025  82 0.211 ± 0.038  83 0.213 ± 0.013  84 1.918± 0.296  85 0.607 ± 0.086 0.399 ± 0.200  87 1.320 ± 0.133 0.548 ± 0.089 88 >20  89 >20  90 >20  91 0.375 ± 0.062 0.300 ± 0.033  92 0.813 ±0.057  93 >20  94 8.801 ± 1.918  95 0.469 ± 0.017  96 0.662 ± 0.0350.627 ± 0.134  97 2.622 ± 0.100  98 0.973 ± 0.099 0.451 ± 0.092  990.896 ± 0.186 1.227 ± 0.364 100 7.072 ± 1.453 102 0.857 ± 0.075 1031.053 ± 0.055 0.299 ± 0.068 104 2.605 ± 0.047 105 0.644 ± 0.025 1060.581 ± 0.038 107 0.669 ± 0.053 109 5.700 ± 0.663 110 0.142 ± 0.0380.161 ± 0.070 111 0.379 ± 0.044 0.459 ± 0.100 112 5.323 ± 0.425 1227.213 ± 0.341 123 9.615 ± 0.339 124 2.137 ± 0.586 125 7.099 ± 2.450

Having now fully described this disclosure, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the disclosure or anyembodiment thereof.

Other embodiments of the disclosure will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

All patents and publications cited herein are fully incorporated byreference in their entirety.

What is claimed is:
 1. A compound having Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein: G isselected from the group consisting of cyano, dihydroxyalkyl, —C(═O)E,—CH(OH)CH(OH)C(═O)E, and —CH(OH)C(═O)E; E is selected from the groupconsisting of hydrogen, hydroxy, alkoxy, dihydroxyalkyl, and—NR^(1a)R^(1b); R^(1a) is selected from the group consisting ofhydrogen, alkyl, aralkyl, (heterocyclo)alkyl, (heteroaryl)alkyl,(amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl,(carboxamido)alkyl, (cyano)alkyl, alkoxyalkyl, hydroxyalkyl, andheteroalkyl; R^(1b) is selected from the group consisting of hydrogenand alkyl; or R^(1a) and R^(1b) taken together with the nitrogen atom towhich they are attached form a 3- to 8-membered optionally substitutedheterocyclo; W¹, W², and W³ are each independently selected from thegroup consisting of N and CR²; with the proviso that at least one of W¹,W², and W³ is N; R² is selected from the group consisting of hydrogen,halo, and alkyl; A is

R^(3a) is selected from the group consisting of hydrogen, alkyl,heteroalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl,(alkoxy)alkyl, optionally substituted cycloalkyl, optionally substitutedheterocyclo, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aralkyl, carboxamido, optionallysubstituted alkylcarbonyl, optionally substituted (alkoxy)carbonyl, and—SO₂R^(6c); R⁴ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl,(dialkylamino)alkyl, optionally substituted aralkyl, optionallysubstituted (heteroaryl)alkyl, optionally substituted (cycloalkyl)alkyl,(cyano)alkyl, (carboxamido)alkyl, —COR^(6a), and —SO₂R^(6b); R^(6a) isselected from the group consisting of alkyl, alkoxy, hydroxyalkyl,optionally substituted cycloalkyl, optionally substituted aryl, amino,alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, and(dialkylamino)alkyl; R^(6b) is selected from the group consisting ofalkyl, optionally substituted cycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; R^(6c) is selected from the groupconsisting of alkyl, optionally substituted cycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; R⁵ is selectedfrom the group consisting of hydrogen, halo, alkyl, hydroxyalkyl, cyano,heterocyclo, and —X—R⁷; X is selected from the group consisting of —O—,—NR^(8a)—, and —(CH₂)_(t)—Y²—; Y² is selected from the group consistingof —O— and —NR^(8b)—; t is 1, 2, 3 or 4; R⁷ is selected from the groupconsisting of hydrogen, alkyl, hydroxyalkyl,

R^(8a) is selected from the group consisting of hydrogen and alkyl;R^(8b) is selected from the group consisting of hydrogen and alkyl; orR^(8b) and R⁷ taken together with the nitrogen atom to which they areattached form a 3- to 8-membered optionally substituted heterocyclo; R⁹is selected from the group consisting of hydrogen, alkyl, andhydroxyalkyl; and R^(10a) and R^(10b) are independently selected fromthe group consisting of hydrogen and alkyl; or R^(10a) and R^(10b) takentogether with the nitrogen atom to which they are attached form a 3- to8-membered optionally substituted heterocyclo.
 2. The compound of claim1, wherein R⁴ is selected from the group consisting of —COR^(6a) and—SO₂R^(6b), or a pharmaceutically acceptable salt or solvate thereof. 3.The compound of claim 1, wherein R^(3a) is selected from the groupconsisting of alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocyclo, optionally substituted aryl, optionallysubstituted heteroaryl, and —SO₂R^(6c), or a pharmaceutically acceptablesalt or solvate thereof.
 4. The compound of claim 3, wherein R^(3a) isoptionally substituted phenyl or (C₁-C₆)alkyl, or a pharmaceuticallyacceptable salt or solvate thereof.
 5. The compound of claim 1, whereinW¹ is N, W² is CH, and W³ is CH, or a pharmaceutically acceptable saltor solvate thereof.
 6. The compound of claim 1, wherein W¹ is N, W² isN, and W³ is CH, or a pharmaceutically acceptable salt or solvatethereof.
 7. The compound of claim 1, wherein G is dihydroxyalkylselected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.
 8. Thecompound of claim 1, wherein G is —C(═O)E, or a pharmaceuticallyacceptable salt or solvate thereof.
 9. The compound of claim 1, whereinG is —CH(OH)CH(OH)C(═O)E selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.
 10. Thecompound of claim 1, wherein R⁵ is selected from the group consisting ofhydrogen, hydroxyalkyl, and —X—R⁷, or a pharmaceutically acceptable saltor solvate thereof.
 11. The compound of claim 10, wherein R⁵ is —X—R⁷,or a pharmaceutically acceptable salt or solvate thereof, wherein X is—O—, —NH—, or —CH₂NH—; and R⁷ is selected from the group consisting of:


12. The compound of claim 1, wherein R⁵ is hydroxyalkyl, wherein saidhydroxyalkyl is monohydroxyalkyl or dihydroxyalkyl, or apharmaceutically acceptable salt or solvate thereof.
 13. The compound ofclaim 1, wherein R⁵ is hydroxyalkyl, wherein said hydroxyalkyl isdihydroxyalkyl selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.
 14. Thecompound of claim 1 selected from the group consisting of: tert-Butyl7-(6-carbamoylpyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxylate;tert-Butyl(S)-7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxylate;tert-butyl(S)-7-(4-((1-amino-1-oxopropan-2-yl)amino)-6-carbamoylpyrimidin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxylate;6-(1-(4-(Trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)picolinamide;6-(4-Methyl-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)picolinamide;(S)-1-(6-(1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyridin-2-yl)ethane-1,2-diol;(S)-1-(6-(4-(cyclopropylmethyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyridin-2-yl)ethane-1,2-diol;(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyrimidine-4-carboxamide;(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-(cyclopropylmethyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyrimidine-4-carboxamide;(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-methyl-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyrimidine-4-carboxamide;6(4-Acetyl-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)picolinamide;7-(6-Carbamoylpyridin-2-yl)-N,N-diethyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxamide;6-(4-(Cyclopropanecarbonyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)picolinamide;(S)-1-(1-cyclohexyl-7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)ethan-1-one;(S)-1-(6-(4-(methylsulfonyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyridin-2-yl)ethane-1,2-diol;(S)-1-(7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)ethan-1-one;(S)-7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-N-ethyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxamide;(S)-7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxamide;(S)-1-(7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2-hydroxyethan-1-one;(S)-1-(7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2-(dimethylamino)ethan-1-one;6-(4-(Cyanomethyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)picolinamide;(S)-2-(7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)acetamide;(S)-2-(1-cyclohexyl-7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)acetamide;(S)-2-(7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-N-methylacetamide;(S)-2-(7-(6-(1,2-dihydroxyethyl)pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)acetonitrile;(S)-1-(6-(4-((1H-imidazol-2-yl)methyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyridin-2-yl)ethane-1,2-diol;6-(4-Allyl-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)picolinamide;6-(4-(2,3-Dihydroxypropyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)picolinamide;(S)-6-(4-(cyclopropylmethyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)-4-(1,2-dihydroxyethyl)picolinonitrile;(S)-6-(4-(cyclopropylmethyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)-4-(1,2-dihydroxyethyl)picolinamide;(S)-4-(4-(cyclopropylmethyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)-6-(1,2-dihydroxyethyl)picolinamide;(S)-1-(6-(1-isobutyl-4-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyridin-2-yl)ethane-1,2-diol;and(2R,3S)-2,3-dihydroxy-3-(6-(1-isobutyl-4-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyridin-2-yl)propanamide,or a pharmaceutically acceptable salt or solvate thereof.
 15. Thecompound as claimed in claim 1, or a pharmaceutically acceptable salt orsolvate thereof, wherein the compound is ³H, ¹¹C, or ¹⁴C radiolabeled.16. A pharmaceutical composition comprising the compound of claim 1, ora pharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier.
 17. A method for treating oralleviating pain in a mammal, comprising administering an effectiveamount of a compound as claimed in claim 1, or a pharmaceuticallyacceptable salt or solvate thereof, to a mammal in need thereof.
 18. Themethod of claim 17, wherein said pain is selected from the groupconsisting of chronic pain, inflammatory pain, neuropathic pain, acutepain, and surgical pain.